285 publications found
2024
The Janus face of endogenous neuronal tPA: promoting self-protection and worsening the death of neighboring neurons.
Prunotto P, Marie P, Lebouvier L, Hommet Y, Vivien D, Ali C
Cell Death Dis 2041-4889
PMID : 38609369
KEYWORDS : Animals|Mice|Endothelial Cells|Ischemic Stroke|N-Methylaspartate|pharmacology|Neurons|Neurotoxicity Syndromes|Tissue Plasminogen Activator
Show abstract [+]
Recombinant tissue-type plasminogen activator (r-tPA/Actilyse) stands as the prevailing pharmacological solution for treating ischemic stroke patients, of whom because their endogenous circulating tPA alone is not sufficient to rescue reperfusion and to promote favorable outcome. Beyond the tPA contributed by circulating endothelial cells and hepatocytes, neurons also express tPA, sparking debates regarding its impact on neuronal fate ranging from pro-survival to neurotoxic properties. In order to investigate the role of neuronal tPA during brain injuries, we developed models leading to its conditional deletion in neurons, employing AAV9-pPlat-GFP and AAV9-pPlat-Cre-GFP along with tPA floxed mice. These models were subjected to N-methyl-D-aspartate (NMDA)-induced excitotoxicity or thromboembolic ischemic stroke in mice. Initially, we established that our AAV9 constructs selectively transduce neurons, bypassing other brain cell types. Subsequently, we demonstrated that tPA-expressing neurons exhibit greater resistance against NMDA-induced excitotoxicity compared to tPA negative neurons. The targeted removal of tPA in neurons heightened the susceptibility of these neurons to cell death and prevented a paracrine neurotoxic effect on tPA non-expressing neurons. Under ischemic conditions, the self-neuroprotective influence of tPA encompassed both excitatory (GFP+/Tbr1+) and inhibitory (GFP+/GABA+) neurons. Our data indicate that endogenous neuronal tPA is a protective or deleterious factor against neuronal death in an excitotoxic/ischemic context, depending on whether it acts as an autocrine or a paracrine mediator.
Intestinal MAdCAM-1 imaging as biomarker for prognostic in murine models of multiple sclerosis.
Baudron E, Martinez de Lizarrondo S, Gauberti M, Delaunay-Piednoir B, Fournier AP, Vivien D, Docagne F, Bardou I
Brain Behav Immun 1090-2139
PMID : 38604270
Show abstract [+]
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Recent evidence suggests that lymphocyte trafficking in the intestines could play a key role in its etiology. Nevertheless, it is not clear how intestinal tissue is involved in the disease onset nor its evolution. In the present study, we aimed to evaluate intestinal inflammation dynamic throughout the disease course and its potential impact on disease progression.
Pharmacological inhibition of mTORC1 reduces neural death and damage volume after MCAO by modulating microglial reactivity.
Villa-González M, Rubio M, Martín-López G, Mallavibarrena PR, Vallés-Saiz L, Vivien D, Wandosell F, Pérez-Álvarez MJ
Biol Direct 1745-6150
PMID : 38582839
KEYWORDS : Mice|Animals|Microglia|Mechanistic Target of Rapamycin Complex 1|Neuroinflammatory Diseases|Brain Ischemia|drug therapy|TOR Serine-Threonine Kinases|therapeutic use|Ischemia|Sirolimus|pharmacology|Mammals
Show abstract [+]
Ischemic stroke is a sudden and acute disease characterized by neuronal death, increment of reactive gliosis (reactive microglia and astrocytes), and a severe inflammatory process. Neuroinflammation is an early event after cerebral ischemia, with microglia playing a leading role. Reactive microglia involve functional and morphological changes that drive a wide variety of phenotypes. In this context, deciphering the molecular mechanisms underlying such reactive microglial is essential to devise strategies to protect neurons and maintain certain brain functions affected by early neuroinflammation after ischemia. Here, we studied the role of mammalian target of rapamycin (mTOR) activity in the microglial response using a murine model of cerebral ischemia in the acute phase. We also determined the therapeutic relevance of the pharmacological administration of rapamycin, a mTOR inhibitor, before and after ischemic injury. Our data show that rapamycin, administered before or after brain ischemia induction, reduced the volume of brain damage and neuronal loss by attenuating the microglial response. Therefore, our findings indicate that the pharmacological inhibition of mTORC1 in the acute phase of ischemia may provide an alternative strategy to reduce neuronal damage through attenuation of the associated neuroinflammation.
CNS-associated macrophages contribute to intracerebral aneurysm pathophysiology.
Glavan M, Jelic A, Levard D, Frösen J, Keränen S, Franx BAA, Bras AR, Louet ER, Dénes Á, Merlini M, Vivien D, Rubio M
Acta Neuropathol Commun 2051-5960
PMID : 38500201
KEYWORDS : Mice|Animals|Humans|Intracranial Aneurysm|etiology|Inflammation|pathology|Central Nervous System|metabolism|Risk Factors|Macrophages|metabolism|Aneurysm, Ruptured|complications
Show abstract [+]
Intracerebral aneurysms (IAs) are pathological dilatations of cerebral arteries whose rupture leads to subarachnoid hemorrhage, a significant cause of disability and death. Inflammation is recognized as a critical contributor to the formation, growth, and rupture of IAs; however, its precise actors have not yet been fully elucidated. Here, we report CNS-associated macrophages (CAMs), also known as border-associated macrophages, as one of the key players in IA pathogenesis, acting as critical mediators of inflammatory processes related to IA ruptures. Using a new mouse model of middle cerebral artery (MCA) aneurysms we show that CAMs accumulate in the IA walls. This finding was confirmed in a human MCA aneurysm obtained after surgical clipping, together with other pathological characteristics found in the experimental model including morphological changes and inflammatory cell infiltration. In addition, in vivo longitudinal molecular MRI studies revealed vascular inflammation strongly associated with the aneurysm area, i.e., high expression of VCAM-1 and P-selectin adhesion molecules, which precedes and predicts the bleeding extent in the case of IA rupture. Specific CAM depletion by intracerebroventricular injection of clodronate liposomes prior to IA induction reduced IA formation and rupture rate. Moreover, the absence of CAMs ameliorated the outcome severity of IA ruptures resulting in smaller hemorrhages, accompanied by reduced neutrophil infiltration. Our data shed light on the unexplored role of CAMs as main actors orchestrating the progression of IAs towards a rupture-prone state.
Modulation of Abundance and Location of High-Mobility Group Box 1 in Human Microglia and Macrophages under Oxygen-Glucose Deprivation.
Bielawski PB, Zhang I, Correa-Paz C, Campos F, Migliavacca M, Polo E, Del Pino P, Pelaz B, Vivien D, Maysinger D
ACS Pharmacol Transl Sci 2575-9108
PMID : 38481701
Show abstract [+]
While stroke represents one of the main causes of death worldwide, available effective drug treatment options remain limited to classic thrombolysis with recombinant tissue plasminogen activator (rtPA) for arterial-clot occlusion. Following stroke, multiple pathways become engaged in producing a vicious proinflammatory cycle through the release of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) and heat shock protein 70 kDa (HSP72). HMGB1, in particular, can activate proinflammatory cytokine production when acetylated (AcHMGB1), a form that prefers cytosolic localization and extracellular release. This study aimed at determining how HMGB1 and HSP72 are modulated and affected following treatment with the anti-inflammatory compound resveratrol and novel platelet membrane-derived nanocarriers loaded with rtPA (CSM@rtPA) recently developed by our group for ischemic artery recanalization. Under ischemic conditions of oxygen-glucose deprivation (OGD), nuclear abundance of HMGB1 and AcHMGB1 in microglia and macrophages decreased, whereas treatment with CSM@rtPA did not alter nuclear or cytosolic abundance. Resveratrol treatment markedly increased the cytosolic abundance of HSP72 in microglia. Using proximity ligation assays, we determined that HSP72 interacted with HMGB1 and with acetylated HMGB1. The interaction was differentially affected under the OGD conditions. Resveratrol treatment under the OGD further decreased HSP72-HMGB1 interactions, whereas, in contrast, treatment increased HSP72-AcHMGB1 interactions in microglia. This study points out a salient molecular interaction suited for a two-pronged nanotherapeutic intervention in stroke: enhancement of rtPA's thrombolytic activity and modulation of cytosolic interactions between HMGB1 and HSP72 by resveratrol.
Associations Between Repetitive Negative Thinking and Objective and Subjective Sleep Health in Cognitively Healthy Older Adults.
Munns LB, Demnitz-King H, André C, Rehel S, Ourry V, de La Sayette V, Vivien D, Chételat G, Rauchs G, Marchant NL,
Nat Sci Sleep 1179-1608
PMID : 38476462
Show abstract [+]
Poor sleep and high levels of repetitive negative thinking (RNT), including future-directed (ie, worry) and past-directed (ie, brooding) negative thoughts, have been associated with markers of dementia risk. The relationship between RNT and sleep health in older adults is unknown. This study aimed to investigate this association and its specificities including multiple dimensions of objective and subjective sleep.
N-Acetylcysteine To Reduce Mortality For Patients Requiring Cardiac Catheterization or Cardiac Surgery: A Systematic Review And Meta-Analysis.
Gakuba C, Dumitrascu AD, Marsan PE, Legallois D, Hanouz JL, Vivien D, Martinez De Lizarrondo S, Gauberti M, Cerasuolo D
J Cardiovasc Pharmacol 1533-4023
PMID : 38467037
Show abstract [+]
Multimers of von Willebrand factor (VWF) play a critical role in various processes inducing morbidity and mortality in cardiovascular risk patients. With the ability to reduce VWF multimers, N-acetylcysteine (NAC) could reduce mortality in patients undergoing coronary catheterization or cardiac surgery. However, its impact in perioperative period has never been studied so far in regard of its potential cardiovascular benefits. Then, four databases were searched for randomized controlled trials that compared in-hospital mortality between an experimental group, with NAC, and a control group without NAC, in patients undergoing coronary catheterization or cardiac surgery. The primary efficacy outcome was in-hospital mortality. Secondary outcomes were the occurrence of thrombotic events, major cardiovascular events, myocardial infarction, and contrast induced nephropathy. The safety outcome was occurrence of hemorrhagic events. Nineteen studies totaling 3718 patients were included. Pooled analysis demonstrated a reduction of in-hospital mortality associated with NAC: Odds Ratio (OR), 0.60; 95% CI, 0.39-0.92; P=0.02. The occurrence of secondary outcomes was not significantly reduced with NAC except for contrast-induced nephropathy. No difference was reported for hemorrhagic events. Subgroup analyses revealed a life-saving effect of NAC in a dose-dependent manner with reduction of in-hospital mortality for the NAC high-dose group, but not for the NAC standard-dose (<3500 mg) group. In conclusion, without being able to conclude on the nature of the mechanism involved, our review suggests a benefit of NAC in cardiovascular risk patients in perioperative period in terms of mortality and supports prospective confirmatory studies.
Pharmacological preclinical comparison of tenecteplase and alteplase for the treatment of acute stroke.
Correa-Paz C, Pérez-Mato M, Bellemain-Sagnard M, González-Domínguez M, Marie P, Pérez-Gayol L, López-Arias E, Del Pozo-Filíu L, López-Amoedo S, Bugallo-Casal A, Alonso-Alonso ML, Candamo-Lourido M, Santamaría-Cadavid M, Arias-Rivas S, Rodríguez-Yañez M, Iglesias-Rey R, Castillo J, Vivien D, Rubio M, Campos F
J Cereb Blood Flow Metab 1559-7016
PMID : 38436292
Show abstract [+]
Alteplase (rtPA) remains the standard thrombolytic drug for acute ischemic stroke. However, new rtPA-derived molecules, such as tenecteplase (TNK), with prolonged half-lives following a single bolus administration, have been developed. Although TNK is currently under clinical evaluation, the limited preclinical data highlight the need for additional studies to elucidate its benefits. The toxicities of rtPA and TNK were evaluated in endothelial cells, astrocytes, and neuronal cells. In addition, their in vivo efficacy was independently assessed at two research centers using an ischemic thromboembolic mouse model. Both therapies were tested via early (20 and 30 min) and late administration (4 and 4.5 h) after stroke. rtPA, but not TNK, caused cell death only in neuronal cultures. Mice were less sensitive to thrombolytic therapies than humans, requiring doses 10-fold higher than the established clinical dose. A single bolus dose of 2.5 mg/kg TNK led to an infarct reduction similar to perfusion with 10 mg/kg of rtPA. Early administration of TNK decreased the hemorrhagic transformations compared to that by the early administration of rtPA; however, this result was not obtained following late administration. These two independent preclinical studies support the use of TNK as a promising reperfusion alternative to rtPA.
Leptomeningeal collaterals regulate reperfusion in ischemic stroke and rescue the brain from futile recanalization.
Binder NF, El Amki M, Glück C, Middleham W, Reuss AM, Bertolo A, Thurner P, Deffieux T, Lambride C, Epp R, Handelsmann HL, Baumgartner P, Orset C, Bethge P, Kulcsar Z, Aguzzi A, Tanter M, Schmid F, Vivien D, Wyss MT, Luft A, Weller M, Weber B, Wegener S
Neuron 1097-4199
PMID : 38412858
Show abstract [+]
Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet-unknown functions. We applied laser speckle imaging, ultrafast ultrasound, and two-photon microscopy in a thrombin-based mouse model of stroke and fibrinolytic treatment to show that LMCs maintain cerebral autoregulation and allow for gradual reperfusion, resulting in small infarcts. In mice with poor LMCs, distal arterial segments collapse, and deleterious hyperemia causes hemorrhage and mortality after recanalization. In silico analyses confirm the relevance of LMCs for preserving perfusion in the ischemic region. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion and preventing futile recanalization after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for beneficial reperfusion after stroke.
Tissue-plasminogen activator effects on the phenotype of splenic myeloid cells in acute inflammation.
Seillier C, Lesec L, Hélie P, Marie C, Vivien D, Docagne F, Le Mauff B, Toutirais O
J Inflamm (Lond) 1476-9255
PMID : 38355547
Show abstract [+]
Tissue-plasminogen activator (tPA) is a serine protease well known for its fibrinolytic function. Recent studies indicate that tPA could also modulate inflammation via plasmin generation and/or by receptor mediated signalling in vitro. However, the contribution of tPA in inflammatory processes in vivo has not been fully addressed. Therefore, using tPA-deficient mice, we have analysed the effect of lipopolysaccharide (LPS) challenge on the phenotype of myeloid cells including neutrophils, macrophages and dendritic cells (DCs) in spleen. We found that LPS treatment upregulated the frequency of major histocompatibility class two (MHCII+) macrophages but also, paradoxically, induced a deep downregulation of MHCII molecule level on macrophages and on conventional dendritic cells 2 (cDC2). Expression level of the CD11b integrin, known as a tPA receptor, was upregulated by LPS on MHCII+ macrophages and cDC2, suggesting that tPA effects could be amplified during inflammation. In tPA-/- mice under inflammatory conditions, expression of costimulatory CD86 molecules on MHCII+ macrophages was decreased compared to WT mice, while in steady state the expression of MHCII molecules was higher on macrophages. Finally, we reported that tPA deficiency slightly modified the phenotype of DCs and T cells in acute inflammatory conditions. Overall, our findings indicate that in vivo, LPS injection had an unexpectedly bimodal effect on MHCII expression on macrophages and DCs that consequently might affect adaptive immunity. tPA could also participate in the regulation of the T cell response by modulating the levels of CD86 and MHCII molecules on macrophages.
The niche matters: origin, function and fate of CNS-associated macrophages during health and disease.
Dalmau Gasull A, Glavan M, Samawar SKR, Kapupara K, Kelk J, Rubio M, Fumagalli S, Sorokin L, Vivien D, Prinz M
Acta Neuropathol 1432-0533
PMID : 38347231
KEYWORDS : Mice|Animals|Proteomics|Macrophages|pathology|Central Nervous System|pathology|Microglia|Meninges
Show abstract [+]
There are several cellular and acellular structural barriers associated with the brain interfaces, which include the dura, the leptomeninges, the perivascular space and the choroid plexus epithelium. Each structure is enriched by distinct myeloid populations, which mainly originate from erythromyeloid precursors (EMP) in the embryonic yolk sac and seed the CNS during embryogenesis. However, depending on the precise microanatomical environment, resident myeloid cells differ in their marker profile, turnover and the extent to which they can be replenished by blood-derived cells. While some EMP-derived cells seed the parenchyma to become microglia, others engraft the meninges and become CNS-associated macrophages (CAMs), also referred to as border-associated macrophages (BAMs), e.g., leptomeningeal macrophages (MnMΦ). Recent data revealed that MnMΦ migrate into perivascular spaces postnatally where they differentiate into perivascular macrophages (PvMΦ). Under homeostatic conditions in pathogen-free mice, there is virtually no contribution of bone marrow-derived cells to MnMΦ and PvMΦ, but rather to macrophages of the choroid plexus and dura. In neuropathological conditions in which the blood-brain barrier is compromised, however, an influx of bone marrow-derived cells into the CNS can occur, potentially contributing to the pool of CNS myeloid cells. Simultaneously, resident CAMs may also proliferate and undergo transcriptional and proteomic changes, thereby, contributing to the disease outcome. Thus, both resident and infiltrating myeloid cells together act within their microenvironmental niche, but both populations play crucial roles in the overall disease course. Here, we summarize the current understanding of the sources and fates of resident CAMs in health and disease, and the role of the microenvironment in influencing their maintenance and function.
Ischemic Stroke: From Fibrinolysis to Functional Recovery.
Ali C, Vivien D
Neuroscience 1873-7544
PMID : 38301738
Parabiosis Discriminates the Circulating, Endothelial, and Parenchymal Contributions of Endogenous Tissue-Type Plasminogen Activator to Stroke.
Furon J, Lebrun F, Yétim M, Levard D, Marie P, Orset C, Martinez de Lizarrondo S, Vivien D, Ali C
Stroke 1524-4628
PMID : 38288607
KEYWORDS : Animals|Mice|Disease Models, Animal|Endothelial Cells|Endothelium|Mice, Knockout|Stroke|diagnostic imaging|Thrombotic Stroke|Tissue Plasminogen Activator|genetics
Show abstract [+]
Intravenous injection of alteplase, a recombinant tPA (tissue-type plasminogen activator) as a thrombolytic agent has revolutionized ischemic stroke management. However, tPA is a more complex enzyme than expected, being for instance able to promote thrombolysis, but at the same time, also able to influence neuronal survival and to affect the integrity of the blood-brain barrier. Accordingly, the respective impact of endogenous tPA expressed/present in the brain parenchyma versus in the circulation during stroke remains debated.
Multimodal neuroimaging correlates of spectral power in NREM sleep delta sub-bands in cognitively unimpaired older adults.
Champetier P, André C, Rehel S, Ourry V, Landeau B, Mézenge F, Roquet D, Vivien D, de La Sayette V, Chételat G, Rauchs G,
Sleep 1550-9109
PMID : 38227830
KEYWORDS : Humans|Aged|Sleep, Slow-Wave|Sleep|Sleep Stages|Polysomnography|Electroencephalography|Brain|diagnostic imaging|Neuroimaging
Show abstract [+]
In aging, reduced delta power (0.5-4 Hz) during N2 and N3 sleep has been associated with gray matter (GM) atrophy and hypometabolism within frontal regions. Some studies have also reported associations between N2 and N3 sleep delta power in specific sub-bands and amyloid pathology. Our objective was to better understand the relationships between spectral power in delta sub-bands during N2-N3 sleep and brain integrity using multimodal neuroimaging.
Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages.
Lebrun F, Levard D, Lemarchand E, Yetim M, Furon J, Potzeha F, Marie P, Lesept F, Blanc M, Haelewyn B, Rubio M, Letourneur A, Violle N, Orset C, Vivien D
Blood Adv 2473-9537
PMID : 38190586
KEYWORDS : Mice|Animals|Humans|Tissue Plasminogen Activator|pharmacology|Mice, Obese|Stroke|drug therapy|Hemorrhage|Inflammation|drug therapy|Ischemic Stroke|complications|Hyperglycemia|complications
Show abstract [+]
The pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.
Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke.
Migliavacca M, Correa-Paz C, Pérez-Mato M, Bielawski PB, Zhang I, Marie P, Hervella P, Rubio M, Maysinger D, Vivien D, Del Pino P, Pelaz B, Polo E, Campos F
J Nanobiotechnology 1477-3155
PMID : 38166940
KEYWORDS : Humans|Mice|Animals|Tissue Plasminogen Activator|Ischemic Stroke|Fibrinolytic Agents|pharmacology|Thrombolytic Therapy|adverse effects|Stroke|drug therapy|Brain Ischemia|drug therapy
Show abstract [+]
Intravenous administration of fibrinolytic drugs, such as recombinant tissue plasminogen activator (rtPA) is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and risk of hemorrhagic transformations. Platelet membrane-based nanocarriers have received increasing attention for ischemic stroke therapies, as they have natural thrombus-targeting activity, can prolong half-life of the fibrinolytic therapy, and reduce side effects. In this study we have gone further in developing platelet-derived nanocarriers (defined as cellsomes) to encapsulate and protect rtPA from degradation. Following lyophilization and characterization, their formulation properties, biocompatibility, therapeutic effect, and risk of hemorrhages were later investigated in a thromboembolic model of stroke in mice.
Dynamics of cerebral blood volume during and after middle cerebral artery occlusion in rats - Comparison between ultrafast ultrasound and dynamic susceptibility contrast-enhanced MRI measurements.
Franx BA, Lebrun F, Chin Joe Kie L, Deffieux T, Vivien D, Bonnard T, Dijkhuizen RM,
J Cereb Blood Flow Metab 1559-7016
PMID : 38126356
KEYWORDS : Rats|Animals|Cerebral Blood Volume|Infarction, Middle Cerebral Artery|diagnostic imaging|Magnetic Resonance Imaging|methods|Brain|diagnostic imaging|Stroke|Cerebrovascular Circulation|physiology|Contrast Media
Show abstract [+]
Tomographic perfusion imaging techniques are integral to translational stroke research paradigms that advance our understanding of the disease. Functional ultrasound (fUS) is an emerging technique that informs on cerebral blood volume (CBV) through ultrasensitive Doppler and flow velocity (CBFv) through ultrafast localization microscopy. It is not known how experimental results compare with a classical CBV-probing technique such as dynamic susceptibility contrast-enhanced perfusion MRI (DSC-MRI). To that end, we assessed hemodynamics based on uUS (n = 6) or DSC-MRI (n = 7) before, during and up to three hours after 90-minute filament-induced middle cerebral artery occlusion (MCAO) in rats. Recanalization was followed by a brief hyperperfusion response, after which CBV and CBFv temporarily normalized but progressively declined after one hour in the lesion territory. DSC-MRI data corroborated the incomplete restoration of CBV after recanalization, which may have been caused by the free-breathing anesthetic regimen. During occlusion, MCAO-induced hypoperfusion was more discrepant between either technique, likely attributable to artefactual signal mechanisms related to slow flow, and processing algorithms employed for either technique. In vivo uUS- and DSC-MRI-derived measures of CBV enable serial whole-brain assessment of post-stroke hemodynamics, but readouts from both techniques need to be interpreted cautiously in situations of very low blood flow.
2023
rtPA-loaded fucoidan polymer microbubbles for the targeted treatment of stroke.
Fournier L, Abioui-Mourgues M, Chabouh G, Aid R, Taille T, Couture O, Vivien D, Orset C, Chauvierre C
Biomaterials 1878-5905
PMID : 37952499
KEYWORDS : Humans|Animals|Mice|Tissue Plasminogen Activator|therapeutic use|Microbubbles|Polymers|Fibrinolytic Agents|therapeutic use|Stroke|drug therapy
Show abstract [+]
Systemic injection of thrombolytic drugs is the gold standard treatment for non-invasive blood clot resolution. The most serious risks associated with the intravenous injection of tissue plasminogen activator-like proteins are the bleeding complication and the dose related neurotoxicity. Indeed, the drug has to be injected in high concentrations due to its short half-life, the presence of its natural blood inhibitor (PAI-1) and the fast hepatic clearance (0.9 mg/kg in humans, 10 mg/kg in mouse models). Overall, there is a serious need for a dose-reduced targeted treatment to overcome these issues. We present in this article a new acoustic cavitation-based method for polymer MBs synthesis, three times faster than current hydrodynamic-cavitation method. The generated MBs are ultrasound responsive, stable and biocompatible. Their functionalization enabled the efficient and targeted treatment of stroke, without side effects. The stabilizing shell of the MBs is composed of Poly-Isobutyl Cyanoacrylate (PIBCA), copolymerized with fucoidan. Widely studied for its targeting properties, fucoidan exhibit a nanomolar affinity for activated endothelium and activated platelets (P-selectins). Secondly, the thrombolytic agent (rtPA) was loaded onto microbubbles (MBs) with a simple adsorption protocol. Hence, the present study validated the in vivo efficiency of rtPA-loaded Fuco MBs to be over 50 % more efficient than regular free rtPA injection for stroke resolution. In addition, the relative injected rtPA grafted onto targeting MBs was 1/10th of the standard effective dose (1 mg/kg in mouse). As a result, no hemorrhagic event, BBB leakage nor unexpected tissue distribution were observed.
A multi-disciplinary commentary on preclinical research to investigate vascular contributions to dementia.
Sri S, Greenstein A, Granata A, Collcutt A, Jochems ACC, McColl BW, Castro BD, Webber C, Reyes CA, Hall C, Lawrence CB, Hawkes C, Pegasiou-Davies CM, Gibson C, Crawford CL, Smith C, Vivien D, McLean FH, Wiseman F, Brezzo G, Lalli G, Pritchard HAT, Markus HS, Bravo-Ferrer I, Taylor J, Leiper J, Berwick J, Gan J, Gallacher J, Moss J, Goense J, McMullan L, Work L, Evans L, Stringer MS, Ashford M, Abulfadl M, Conlon N, Malhotra P, Bath P, Canter R, Brown R, Ince S, Anderle S, Young S, Quick S, Szymkowiak S, Hill S, Allan S, Wang T, Quinn T, Procter T, Farr TD, Zhao X, Yang Z, Hainsworth AH, Wardlaw JM
Cereb Circ Cogn Behav 2666-2450
PMID : 37941765
Show abstract [+]
Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis. This review by a multidisciplinary, diverse (in terms of sex, geography and career stage), cross-institute team provides a perspective on limitations to current VCI models and recommendations for improving translation and reproducibility. We discuss reproducibility, clinical features of VCI and corresponding assessments in models, human pathology, bioinformatics approaches, and data sharing. We offer recommendations for future research, particularly focusing on small vessel disease as a main underpinning disorder.
Effect of cognitive reserve on the association between slow wave sleep and cognition in community-dwelling older adults.
Ourry V, Rehel S, André C, Mary A, Paly L, Delarue M, Requier F, Hendy A, Collette F, Marchant NL, Felisatti F, Palix C, Vivien D, de la Sayette V, Chételat G, Gonneaud J, Rauchs G,
Aging (Albany NY) 1945-4589
PMID : 37770186
KEYWORDS : Aged|Humans|Cognition|Cognitive Reserve|Independent Living|Neuropsychological Tests|Sleep|Sleep, Slow-Wave
Show abstract [+]
Sleep, especially slow wave sleep (SWS), is essential for cognitive functioning and is reduced in aging. The impact of sleep quality on cognition is variable, especially in aging. Cognitive reserve (CR) may be an important modulator of these effects. We aimed at investigating this question to better identify individuals in whom sleep disturbances might have greater behavioral consequences. Polysomnography and neuropsychological assessments were performed in 135 cognitively intact older adults (mean age ± SD: 69.4 ± 3.8y) from the Age-Well randomized controlled trial (baseline data). Two measures of cognitive engagement throughout life were used as CR proxies. Linear regression analyses were performed between the proportion of SWS, and executive function and episodic memory composite scores. Then, interaction analyses between SWS and CR proxies on cognition were conducted to assess the possible impact of CR on these links. SWS was positively associated with episodic memory, but not with executive function. CR proxies modulated the associations between SWS and both executive and episodic memory performance. Specifically, individuals with higher CR were able to maintain cognitive performance despite low amounts of SWS. This study provides the first evidence that CR may protect against the deleterious effects of age-related sleep changes on cognition.
Microsurgery and Endovascular Therapy for Distal Anterior Cerebral Artery Aneurysm: A Multicenter Retrospective Cohort Study.
Metayer T, Gilard V, Piotin M, Emery E, Borha A, Robichon E, Briant AR, Derrey S, Vivien D, Gaberel T
World Neurosurg 1878-8769
PMID : 37451360
Show abstract [+]
Distal anterior cerebral aneurysm (DACA) represents 4% of intracranial aneurysms. Two treatment modalities are available: microsurgery and endovascular therapy (EVT).
Association of Sleep-Disordered Breathing and Medial Temporal Lobe Atrophy in Cognitively Unimpaired Amyloid-Positive Older Adults.
André C, Kuhn E, Rehel S, Ourry V, Demeilliez-Servouin S, Palix C, Felisatti F, Champetier P, Dautricourt S, Yushkevich P, Vivien D, de La Sayette V, Chételat G, de Flores R, Rauchs G,
Neurology 1526-632X
PMID : 37258299
KEYWORDS : Humans|Female|Aged|Alzheimer Disease|Temporal Lobe|metabolism|Acrylates|Amyloid|metabolism|Magnetic Resonance Imaging|Amyloidogenic Proteins|Atrophy|Positron-Emission Tomography|Amyloid beta-Peptides|metabolism|Cognitive Dysfunction
Show abstract [+]
Sleep disordered breathing (SDB) has been related to amyloid deposition and an increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB severity, medial temporal lobe subregions, and episodic memory performance in cognitively unimpaired older adults.
Association of the Informant-Reported Memory Decline With Cognitive and Brain Deterioration Through the Alzheimer Clinical Continuum.
Kuhn E, Perrotin A, La Joie R, Touron E, Dautricourt S, Vanhoutte M, Vivien D, de La Sayette V, Chételat G,
Neurology 1526-632X
PMID : 37085328
KEYWORDS : Aged|Female|Humans|Middle Aged|Alzheimer Disease|psychology|Amyloid|Amyloid beta-Peptides|metabolism|Biomarkers|Brain|metabolism|Cognition|Cognitive Dysfunction|psychology|Cross-Sectional Studies|Memory Disorders|Positron-Emission Tomography
Show abstract [+]
Studies are sparse regarding the association between the informant-reported subjective memory decline (informant report) and Alzheimer disease (AD) biomarkers. This study thus aimed at determining the clinical relevance of the informant report throughout the AD clinical continuum, by assessing its specific relationships with amyloid deposition, cognition, and neurodegeneration.
Respective influence of beta-amyloid and APOE ε4 genotype on medial temporal lobe subregions in cognitively unimpaired older adults.
de Flores R, Demeilliez-Servouin S, Kuhn E, Chauveau L, Landeau B, Delcroix N, Gonneaud J, Vivien D, Chételat G,
Neurobiol Dis 1095-953X
PMID : 37061167
KEYWORDS : Aged|Humans|Alzheimer Disease|diagnostic imaging|Amyloid beta-Peptides|metabolism|Apolipoprotein E4|genetics|Atrophy|pathology|Genotype|Magnetic Resonance Imaging|methods|Positron-Emission Tomography|tau Proteins|metabolism|Temporal Lobe|metabolism
Show abstract [+]
Medial temporal lobe (MTL) subregions are differentially affected in Alzheimer's disease (AD), with a specific involvement of the entorhinal cortex (ERC), perirhinal cortex and hippocampal cornu ammonis (CA)1. While amyloid (Aβ) and APOEε4 are respectively the first molecular change and the main genetic risk factor in AD, their links with MTL atrophy remain relatively unclear. Our aim was to uncover these effects using baseline data from 130 participants included in the Age-Well study, for whom ultra-high-resolution structural MRI, amyloid-PET and APOEε4 genotype were available. No volume differences were observed between Aβ + (n = 24) and Aβ- (n = 103), nor between APOE4+ (n = 35) and APOE4- (n = 95) participants. However, our analyses showed that both Aβ and APOEε4 status interacted with age on CA1, which is known to be specifically atrophied in early AD. In addition, APOEε4 status moderated the effects of age on other subregions (subiculum, ERC), suggesting a more important contribution of APOEε4 than Aβ to MTL atrophy in cognitively unimpaired population. These results are crucial to develop MRI-based biomarkers to detect early AD.
The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα.
Griem-Krey N, Klein AB, Clausen BH, Namini MR, Nielsen PV, Bhuiyan M, Nagaraja RY, De Silva TM, Sobey CG, Cheng HC, Orset C, Vivien D, Lambertsen KL, Clarkson AN, Wellendorph P
J Cereb Blood Flow Metab 1559-7016
PMID : 37026450
KEYWORDS : Mice|Animals|Sodium Oxybate|metabolism|Calcium-Calmodulin-Dependent Protein Kinase Type 2|metabolism|Cognition|Stroke
Show abstract [+]
Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a major contributor to physiological and pathological glutamate-mediated Ca2+ signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented γ-hydroxybutyrate (GHB) ligands as the first small molecules selectively targeting and stabilizing the CaMKIIα hub domain. Here, we report that the cyclic GHB analogue 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), improves sensorimotor function after experimental stroke in mice when administered at a clinically relevant time and in combination with alteplase. Further, we observed improved hippocampal neuronal activity and working memory after stroke. On the biochemical level, we observed that hub modulation by HOCPCA results in differential effects on distinct CaMKII pools, ultimately alleviating aberrant CaMKII signalling after cerebral ischemia. As such, HOCPCA normalised cytosolic Thr286 autophosphorylation after ischemia in mice and downregulated ischemia-specific expression of a constitutively active CaMKII kinase proteolytic fragment. Previous studies suggest holoenzyme stabilisation as a potential mechanism, yet a causal link to in vivo findings requires further studies. Similarly, HOCPCA's effects on dampening inflammatory changes require further investigation as an underlying protective mechanism. HOCPCA's selectivity and absence of effects on physiological CaMKII signalling highlight pharmacological modulation of the CaMKIIα hub domain as an attractive neuroprotective strategy.
Clipping Versus Coiling for Ruptured MCA Aneurysms Associated with Intracerebral Hematoma Requiring Surgical Evacuation.
Metayer T, Dumot C, Bernard F, Le Reste PJ, Bernat AL, Cebula H, Mallereau CH, Peltier C, le Guerinel C, Vivien D, Piotin M, Emery E, Gillard V, Leclerc A, Magro E, Proust F, Pelissou-Guyotat I, Derrey S, Aldea S, Barbier C, Borha A, Nadin L, Briant AR, Gaberel T
Neurocrit Care 1556-0961
PMID : 36991178
KEYWORDS : Adult|Humans|Cohort Studies|Retrospective Studies|Treatment Outcome|Embolization, Therapeutic|Cerebral Hemorrhage|complications|Intracranial Aneurysm|complications|Hematoma|surgery|Stroke|therapy|Brain Ischemia|therapy|Aneurysm, Ruptured|complications
Show abstract [+]
Ruptured middle cerebral artery aneurysm (MCAa) can lead to intracerebral hematoma, and surgical evacuation can be performed in these cases. MCAa can be treated by clipping or before by endovascular therapy (EVT). Our objective was to compare the impact on the functional outcome of MCAa in patients with intracerebral hematoma requiring evacuation.
Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors.
Furon J, Yetim M, Pouettre E, Martinez de Lizarrondo S, Maubert E, Hommet Y, Lebouvier L, Zheng Z, Ali C, Vivien D
Fluids Barriers CNS 2045-8118
PMID : 36737775
KEYWORDS : Mice|Animals|Tissue Plasminogen Activator|N-Methylaspartate|pharmacology|Endothelial Cells|metabolism|Neurovascular Coupling|Brain|metabolism|Receptors, N-Methyl-D-Aspartate|metabolism|Mice, Knockout|Liver|metabolism
Show abstract [+]
Regulation of cerebral blood flow (CBF) directly influence brain functions and dysfunctions and involves complex mechanisms, including neurovascular coupling (NVC). It was suggested that the serine protease tissue-type plasminogen activator (tPA) could control CNV induced by whisker stimulation in rodents, through its action on N-methyl-D-Aspartate receptors (NMDARs). However, the origin of tPA and the location and mechanism of its action on NMDARs in relation to CNV remained debated.
Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release.
Varangot A, Lebatard S, Bellemain-Sagnard M, Lebouvier L, Hommet Y, Vivien D
Cell Death Dis 2041-4889
PMID : 36650132
KEYWORDS : Mice|Animals|Tissue Plasminogen Activator|genetics|Glutamic Acid|metabolism|Neurons|metabolism|Mice, Transgenic
Show abstract [+]
The discovery of the neuronal expression of the serine protease tissue-type plasminogen activator (tPA) has opened new avenues of research, with important implications in the physiopathology of the central nervous system. For example, the interaction of tPA with synaptic receptors (NMDAR, LRP1, Annexin II, and EGFR) and its role in the maturation of BDNF have been reported to influence synaptic plasticity and neuronal survival. However, the mechanisms regulating the neuronal trafficking of tPA are unknown. Here, using high-resolution live cell imaging and a panel of innovative genetic approaches, we first unmasked the dynamic characteristics of the dendritic and axonal trafficking of tPA-containing vesicles under different paradigms of neuronal activation or inhibition. We then report a constitutive exocytosis of tPA- and VAMP2-positive vesicles, dramatically increased in conditions of neuronal activation, with a pattern which was mainly dendritic and thus post-synaptic. We also observed that the synaptic release of tPA led to an increase of the exocytosis of VGlut1 positive vesicles containing glutamate. Finally, we described alterations of the trafficking and exocytosis of neuronal tPA in cultured cortical neurons prepared from tau-22 transgenic mice (a preclinical model of Alzheimer's disease (AD)). Altogether, these data provide new insights about the neuronal trafficking of tPA, contributing to a better knowledge of the tPA-dependent brain functions and dysfunctions.
Rapid Eye Movement Sleep, Neurodegeneration, and Amyloid Deposition in Aging.
André C, Champetier P, Rehel S, Kuhn E, Touron E, Ourry V, Landeau B, Le Du G, Mézenge F, Segobin S, de la Sayette V, Vivien D, Chételat G, Rauchs G,
Ann Neurol 1531-8249
PMID : 36641644
KEYWORDS : Humans|Female|Aged|Sleep, REM|Amyloid beta-Peptides|metabolism|Brain|pathology|Aging|Alzheimer Disease|diagnostic imaging|Positron-Emission Tomography|methods|Magnetic Resonance Imaging|methods
Show abstract [+]
Rapid eye movement (REM) sleep is markedly altered in Alzheimer's disease (AD), and its reduction in older populations is associated with AD risk. However, little is known about the underlying brain mechanisms. Our objective was to investigate the relationships between REM sleep integrity and amyloid deposition, gray matter volume, and perfusion in aging.
Consequences of General Anesthesia in Infancy on Behavior and Brain Structure.
Salaün JP, Chagnot A, Cachia A, Poirel N, Datin-Dorrière V, Dujarrier C, Lemarchand E, Rolland M, Delalande L, Gressens P, Guillois B, Houdé O, Levard D, Gakuba C, Moyon M, Naveau M, Orliac F, Orliaguet G, Hanouz JL, Agin V, Borst G, Vivien D
Anesth Analg 1526-7598
PMID : 36638508
KEYWORDS : Humans|Child|Adult|Animals|Mice|Brain|diagnostic imaging|Anesthesia, General|adverse effects|Magnetic Resonance Imaging|methods|Memory, Short-Term|Anesthetics
Show abstract [+]
One in 7 children will need general anesthesia (GA) before the age of 3. Brain toxicity of anesthetics is controversial. Our objective was to clarify whether exposure of GA to the developing brain could lead to lasting behavioral and structural brain changes.
Impact of Decompressive Craniectomy on Hemorrhagic Transformation in Malignant Ischemic Stroke in Mice.
Borha A, Lebrun F, Touzé E, Emery E, Vivien D, Gaberel T
Stroke 1524-4628
PMID : 36475467
KEYWORDS : Mice|Animals|Ischemic Stroke|surgery|Decompressive Craniectomy|Tissue Plasminogen Activator|therapeutic use|Stroke|therapy|Thrombectomy|Reperfusion|Brain Ischemia|surgery|Treatment Outcome
Show abstract [+]
Endovascular thrombectomy has changed the management of ischemic stroke. The reperfusion can however lead to a hemorrhagic transformation (HT). Decompressive craniectomy (DC) is a surgical procedure used for malignant ischemic stroke. However, its efficacy was demonstrated before the era of endovascular thrombectomy trials. Here, we hypothesized that DC for ischemic stroke after thrombectomy could lead to a higher risk of HT. We thus evaluated this hypothesis in a mouse model of stroke induced by occlusion of the middle cerebral artery (MCAO) with or without mechanical reperfusion.
Influence of prior intravenous thrombolysis in patients treated with mechanical thrombectomy for M2 occlusions: insight from the Endovascular Treatment in Ischemic Stroke (ETIS) registry.
Le Floch A, Clarençon F, Rouchaud A, Kyheng M, Labreuche J, Sibon I, Boulouis G, Gory B, Richard S, Caroff J, Blanc R, Seners P, Eker OF, Cho TH, Consoli A, Bourcier R, Guillon B, Dargazanli C, Arquizan C, Denier C, Eugene F, Vannier S, Gentric JC, Gauberti M, Naggara O, Rosso C, Turc G, Ozkul-Wermester O, Cognard C, Albucher JF, Timsit S, Bourdain F, Le Bras A, Richter S, Moulin S, Pop R, Heck O, Moreno R, L'Allinec V, Lapergue B, Marnat G,
J Neurointerv Surg 1759-8486
PMID : 36460462
KEYWORDS : Humans|Fibrinolytic Agents|therapeutic use|Thrombolytic Therapy|methods|Ischemic Stroke|drug therapy|Thrombectomy|methods|Retrospective Studies|Treatment Outcome|Stroke|drug therapy|Mechanical Thrombolysis|methods|Registries|Brain Ischemia|drug therapy
Show abstract [+]
Intravenous thrombolysis (IVT) for patients treated with mechanical thrombectomy (MT) for proximal occlusions has recently been questioned through randomized trials. However, few patients with M2 occlusions were included. We investigated the influence of prior IVT for patients presenting M2 occlusions treated with MT in comparison with MT alone.
Age-related changes in fast spindle clustering during non-rapid eye movement sleep and their relevance for memory consolidation.
Champetier P, André C, Weber FD, Rehel S, Ourry V, Laniepce A, Lutz A, Bertran F, Cabé N, Pitel AL, Poisnel G, de la Sayette V, Vivien D, Chételat G, Rauchs G
Sleep 1550-9109
PMID : 36433753
KEYWORDS : Memory Consolidation|Eye Movements|Sleep|Polysomnography|methods|Sleep, Slow-Wave|Electroencephalography
Show abstract [+]
Sleep plays a crucial role in memory consolidation. Recent data in rodents and young adults revealed that fast spindle band power fluctuates at a 0.02-Hz infraslow scale during non-rapid eye movement (NREM) sleep. These fluctuations result from a periodic temporal clustering of spindles and may modulate sleep maintenance and memory consolidation. With age, sleep undergoes substantial changes but age-related changes in spindle clustering have never been investigated. Polysomnography data were collected in 147 older (mean age ± SD: 69.3 ± 4.1 years) and 32 young-middle aged (34.5 ± 10.9 years) adults. Sleep-dependent memory consolidation was assessed in a subsample of 57 older adults using a visuospatial memory task. We analyzed power fluctuations in fast spindle frequency band, detected fast spindles, and quantified their clustering during the night separating encoding and retrieval. Fast spindle band power fluctuated at a 0.02-Hz infraslow scale in young-middle aged and older adults. However, the proportion of clustered fast spindles decreased non-linearly with age (p < .001). This effect was not mediated by NREM sleep fragmentation. The clustering level of fast spindles modulated their characteristics (p < .001). Finally, the mean size of spindle clusters was positively associated with memory consolidation (p = .036) and negatively with NREM sleep micro-arousal density (p = .033). These results suggest that clusters of fast spindles may constitute stable sleep periods promoting off-line processes such as memory consolidation. We emphasize the relevance of considering spindle dynamics, obviously impaired during aging, to understand the impact of age-related sleep changes on memory. Clinical Trial Information: Name: Study in Cognitively Intact Seniors Aiming to Assess the Effects of Meditation Training (Age-Well). URL: https://clinicaltrials.gov/ct2/show/NCT02977819?term=Age-Well&draw=2&rank=1. See STROBE_statement_AGEWELL.doc in supplementary material. Registration: EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.
In mice and humans, brain microvascular contractility matures postnatally.
Slaoui L, Gilbert A, Rancillac A, Delaunay-Piednoir B, Chagnot A, Gerard Q, Letort G, Mailly P, Robil N, Gelot A, Lefebvre M, Favier M, Dias K, Jourdren L, Federici L, Auvity S, Cisternino S, Vivien D, Cohen-Salmon M, Boulay AC
Brain Struct Funct 1863-2661
PMID : 36380034
KEYWORDS : Humans|Mice|Animals|Muscle, Smooth, Vascular|physiology|Endothelial Cells|Brain|blood supply|Muscle Contraction
Show abstract [+]
Although great efforts to characterize the embryonic phase of brain microvascular system development have been made, its postnatal maturation has barely been described. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific or -preferentially expressed transcripts. We found that endothelial cells (EC), vascular smooth muscle cells (VSMC) and fibroblasts (FB) follow specific molecular maturation programs over this time period. Focusing on VSMCs, we showed that the arteriolar VSMC network expands and becomes contractile resulting in a greater cerebral blood flow (CBF), with heterogenous developmental trajectories within cortical regions. Samples of the human brain cortex showed the same postnatal maturation process. Thus, the postnatal phase is a critical period during which arteriolar VSMC contractility required for vessel tone and brain perfusion is acquired and mature.
2022
Neutralizing antibodies against SARS-CoV-2 variants following mRNA booster vaccination in adults older than 65 years.
Durier C, Ninove L, Lefebvre M, Radenne A, Desaint C, Ropers J, Bauer R, Lebbah S, Carette D, Lachatre M, Lecompte AS, Deplanque D, Botelho-Nevers E, Conrad A, Dussol B, Maakaroun-Vermesse Z, Melica G, Nicolas JF, Verdon R, Kiladjian J, Loubet P, Schmidt-Mutter C, Dualé C, Ansart S, Priet S, Levier A, Molino D, Vieillard LV, Parfait B, Lelièvre JD, Tartour E, de Lamballerie X, Launay O ,
Sci Rep 2045-2322
PMID : 36437298
KEYWORDS : Humans|Aged|Aged, 80 and over|Antibodies, Neutralizing|SARS-CoV-2|genetics|Neutralization Tests|Antibodies, Viral|RNA, Messenger|Viral Vaccines|COVID-19|prevention & control|Vaccination
Show abstract [+]
Immune response induced by COVID-19 vaccine booster against delta and omicron variants was assessed in 65 adults (65-84 years old) early aftesr a first booster dose. An increase in SARS-CoV-2 neutralizing antibodies was shown in individuals not previously infected without evidence of an age-related effect, with lower increase in those infected before a single dose of primary vaccination. Of note, humoral response was observed only starting from the 5th day after the boost.
Correction to: The choroid plexus: A door between the blood and the brain for tissue-type plasminogen activator.
Zuba V, Furon J, Bellemain-Sagnard M, de Lazarrondo SM, Lebouvier L, Rubio M, Hommet Y, Gauberti M, Vivien D, Ali C
Fluids Barriers CNS 2045-8118
PMID : 36320083
Publisher Correction: 3D transcranial ultrasound localization microscopy for discrimination between ischemic and hemorrhagic stroke in early phase.
Chavignon A, Hingot V, Orset C, Vivien D, Couture O
Sci Rep 2045-2322
PMID : 36261596
Depressive symptoms in cognitively unimpaired older adults are associated with lower structural and functional integrity in a frontolimbic network.
Touron E, Moulinet I, Kuhn E, Sherif S, Ourry V, Landeau B, Mézenge F, Vivien D, Klimecki OM, Poisnel G, Marchant NL, Chételat G
Mol Psychiatry 1476-5578
PMID : 36258017
KEYWORDS : Humans|Aged|Alzheimer Disease|metabolism|Depression|Brain|metabolism|Gray Matter|metabolism|Neuroimaging|Magnetic Resonance Imaging|Positron-Emission Tomography|methods
Show abstract [+]
Subclinical depressive symptoms are associated with increased risk of Alzheimer's disease (AD), but the brain mechanisms underlying this relationship are still unclear. We aimed to provide a comprehensive overview of the brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults using complementary multimodal neuroimaging data. We included cognitively unimpaired older adults from the baseline data of the primary cohort Age-Well (n = 135), and from the replication cohort ADNI (n = 252). In both cohorts, subclinical depressive symptoms were assessed using the 15-item version of the Geriatric Depression Scale; based on this scale, participants were classified as having depressive symptoms (>0) or not (0). Voxel-wise between-group comparisons were performed to highlight differences in gray matter volume, glucose metabolism and amyloid deposition; as well as white matter integrity (only available in Age-Well). Age-Well participants with subclinical depressive symptoms had lower gray matter volume in the hippocampus and lower white matter integrity in the fornix and the posterior parts of the cingulum and corpus callosum, compared to participants without symptoms. Hippocampal atrophy was recovered in ADNI, where participants with subclinical depressive symptoms also showed glucose hypometabolism in the hippocampus, amygdala, precuneus/posterior cingulate cortex, medial and dorsolateral prefrontal cortex, insula, and temporoparietal cortex. Subclinical depressive symptoms were not associated with brain amyloid deposition in either cohort. Subclinical depressive symptoms in ageing are linked with neurodegeneration biomarkers in the frontolimbic network including brain areas particularly sensitive to AD. The relationship between depressive symptoms and AD may be partly underpinned by neurodegeneration in common brain regions.
The choroid plexus: a door between the blood and the brain for tissue-type plasminogen activator.
Zuba V, Furon J, Bellemain-Sagnard M, Martinez de Lizarrondo S, Lebouvier L, Rubio M, Hommet Y, Gauberti M, Vivien D, Ali C
Fluids Barriers CNS 2045-8118
PMID : 36243724
KEYWORDS : Albumins|metabolism|Animals|Blood-Brain Barrier|metabolism|Brain|metabolism|Choroid Plexus|metabolism|Lipoproteins|metabolism|Mice|Tissue Plasminogen Activator
Show abstract [+]
In the vascular compartment, the serine protease tissue-type plasminogen activator (tPA) promotes fibrinolysis, justifying its clinical use against vasculo-occlusive diseases. Accumulating evidence shows that circulating tPA (endogenous or exogenous) also controls brain physiopathological processes, like cerebrovascular reactivity, blood-brain barrier (BBB) homeostasis, inflammation and neuronal fate. Whether this occurs by direct actions on parenchymal cells and/or indirectly via barriers between the blood and the central nervous system (CNS) remains unclear. Here, we postulated that vascular tPA can reach the brain parenchyma via the blood-cerebrospinal fluid barrier (BCSFB), that relies on choroid plexus (CP) epithelial cells (CPECs).
Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults: The Age-Well Randomized Clinical Trial.
Chételat G, Lutz A, Klimecki O, Frison E, Asselineau J, Schlosser M, Arenaza-Urquijo EM, Mézenge F, Kuhn E, Moulinet I, Touron E, Dautricourt S, André C, Palix C, Ourry V, Felisatti F, Gonneaud J, Landeau B, Rauchs G, Chocat A, Quillard A, Devouge EF, Vuilleumier P, de La Sayette V, Vivien D, Collette F, Poisnel G, Marchant NL,
JAMA Neurol 2168-6157
PMID : 36215061
KEYWORDS : Humans|Male|Female|Aged|Meditation|Life Style|Brain|diagnostic imaging|Dementia|Perfusion
Show abstract [+]
No lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk.
Parvalbumin interneuron-derived tissue-type plasminogen activator shapes perineuronal net structure.
Lépine M, Douceau S, Devienne G, Prunotto P, Lenoir S, Regnauld C, Pouettre E, Piquet J, Lebouvier L, Hommet Y, Maubert E, Agin V, Lambolez B, Cauli B, Ali C, Vivien D
BMC Biol 1741-7007
PMID : 36199089
KEYWORDS : Aggrecans|metabolism|Animals|Chondroitin Sulfate Proteoglycans|metabolism|Extracellular Matrix|metabolism|Fibrinolysin|metabolism|Interneurons|physiology|Mice|Parvalbumins|metabolism|Plasminogen|metabolism|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Perineuronal nets (PNNs) are specialized extracellular matrix structures mainly found around fast-spiking parvalbumin (FS-PV) interneurons. In the adult, their degradation alters FS-PV-driven functions, such as brain plasticity and memory, and altered PNN structures have been found in neurodevelopmental and central nervous system disorders such as Alzheimer's disease, leading to interest in identifying targets able to modify or participate in PNN metabolism. The serine protease tissue-type plasminogen activator (tPA) plays multifaceted roles in brain pathophysiology. However, its cellular expression profile in the brain remains unclear and a possible role in matrix plasticity through PNN remodeling has never been investigated.
Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.
Seillier C, Lesept F, Toutirais O, Potzeha F, Blanc M, Vivien D
Int J Mol Sci 1422-0067
PMID : 36142247
KEYWORDS : Central Nervous System Diseases|drug therapy|Glutamic Acid|metabolism|Humans|Neurons|metabolism|Receptors, N-Methyl-D-Aspartate|metabolism|Synaptic Transmission
Show abstract [+]
The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions such as brain development, neuronal plasticity, maturation along with excitotoxicity, blood-brain barrier integrity, and inflammation. NMDARs have thus emerged as key targets for the treatment of neurological disorders. By their large extracellular regions and complex intracellular structures, NMDARs are modulated by a variety of endogenous and pharmacological compounds. Here, we will present an overview of NMDAR functions on neurons and other important cell types involved in the pathophysiology of neurodegenerative, neurovascular, mental, autoimmune, and neurodevelopmental diseases. We will then discuss past and future development of NMDAR targeting drugs, including innovative and promising new approaches.
Microsurgical Clipping of Middle Cerebral Artery Aneurysms: Complications and Risk Factors for Complications.
Metayer T, Leclerc A, Borha A, Derrey S, Langlois O, Barbier C, Aldea S, le Guerinel C, Piotin M, Vivien D, Briant AR, Emery E, Gaberel T
World Neurosurg 1878-8769
PMID : 36115562
KEYWORDS : Humans|Intracranial Aneurysm|surgery|Retrospective Studies|Endovascular Procedures|Treatment Outcome|Aneurysm, Ruptured|surgery|Microsurgery|adverse effects|Brain Ischemia|surgery|Risk Factors|Hematoma|surgery|Middle Cerebral Artery|surgery
Show abstract [+]
Middle cerebral artery aneurysms (MCAAs) have been considered good candidates for microsurgery. Our objective was to evaluate the risk of complications and the risk factors for complications with microsurgical treatment of MCAAs to better define the indications for microsurgery.
3D transcranial ultrasound localization microscopy for discrimination between ischemic and hemorrhagic stroke in early phase.
Chavignon A, Hingot V, Orset C, Vivien D, Couture O
Sci Rep 2045-2322
PMID : 36028542
KEYWORDS : Animals|Brain Ischemia|Cerebral Hemorrhage|Hemorrhagic Stroke|Ischemia|Ischemic Stroke|Microscopy|Rats|Stroke
Show abstract [+]
Early diagnosis is a critical part of the emergency care of cerebral hemorrhages and ischemia. A rapid and accurate diagnosis of strokes reduces the delays to appropriate treatments and a better functional recovery. Currently, CTscan and MRI are the gold standards with constraints of accessibility, availability, and possibly some contraindications. The development of Ultrasound Localization Microscopy (ULM) has enabled new perspectives to conventional transcranial ultrasound imaging with increased sensitivity, penetration depth, and resolution. The possibility of volumetric imaging has increased the field-of-view and provided a more precise description of the microvascularisation. In this study, rats (n = 9) were subjected to thromboembolic ischemic stroke or intracerebral hemorrhages prior to volumetric ULM at the early phases after onsets. Although the volumetric ULM performed in the early phase of ischemic stroke revealed a large hypoperfused area in the cortical area of the occluded artery, it showed a more diffused hypoperfusion in the hemorrhagic model. Respective computations of a Microvascular Diffusion Index highlighted different patterns of perfusion loss during the first 24 h of these two strokes' subtypes. Our study provides the first proof that this methodology should allow early discrimination between ischemic and hemorrhagic stroke with a potential toward diagnosis and monitoring in clinic.
VWF-targeted thrombolysis to overcome rh-tPA resistance in experimental murine ischemic stroke models.
van Moorsel MVA, de Maat S, Vercruysse K, van Leeuwen EM, Jacqmarcq C, Bonnard T, Vivien D, van der Worp HB, Dijkhuizen RM, Maas C
Blood 1528-0020
PMID : 35960811
KEYWORDS : Mice|Humans|Animals|Tissue Plasminogen Activator|pharmacology|Fibrinolytic Agents|pharmacology|von Willebrand Factor|therapeutic use|Ischemic Stroke|Thrombosis|Thromboembolism|Fibrin|metabolism|Thrombolytic Therapy|Plasminogen|therapeutic use|Stroke|drug therapy
Show abstract [+]
Recombinant human tissue plasminogen activator (rh-tPA) is an important thrombolytic agent for treatment of acute ischemic stroke. It requires fibrin binding for plasminogen activation. In contrast, Microlyse, a novel thrombolytic agent, requires von Willebrand factor (VWF) binding for plasminogen activation. We compared rh-tPA with Microlyse, administered 20 minutes after inducing thrombosis, in 2 randomized blinded acute ischemic stroke mouse models. Thrombosis was induced in the middle cerebral artery with different experimental triggers. Where thrombin infusion generates fibrin-rich thrombi, topical FeCl3 application generates platelet-rich thrombi. In the fibrin-rich model, both rh-tPA and Microlyse increased cortical reperfusion (determined by laser speckle imaging) 10 minutes after therapy administration (35.8 ± 17.1%; P = .001 39.3 ± 13.1%; P < .0001; 15.6 ± 7.5%, respectively, vs vehicle). In addition, both thrombolytic agents reduced cerebral lesion volume (determined by magnetic resonance imaging) after 24 hours (18.9 ± 11.2 mm3; P = .033; 16.1 ± 13.9 mm3; P = .018; 26.6 ± 5.6 mm3, respectively, vs vehicle). In the platelet-rich model, neither rh-tPA nor Microlyse increased cortical reperfusion 10 minutes after therapy (7.6 ± 8.8%; P = .216; 16.3 ± 13.9%; P = .151; 10.1 ± 7.9%, respectively, vs vehicle). However, Microlyse, but not rh-tPA, decreased cerebral lesion volumes (13.9 ± 11.4 mm3; P < .001; 23.6 ± 11.1 mm3; P = .188; 30.3 ± 10.9 mm3, respectively, vs vehicle). These findings support broad applicability of Microlyse in ischemic stroke, irrespective of the thrombus composition.
Persistent neuroinflammation and behavioural deficits after single mild traumatic brain injury.
Drieu A, Lanquetin A, Prunotto P, Gulhan Z, Pédron S, Vegliante G, Tolomeo D, Serrière S, Vercouillie J, Galineau L, Tauber C, Kuhnast B, Rubio M, Zanier ER, Levard D, Chalon S, Vivien D, Ali C
J Cereb Blood Flow Metab 1559-7016
PMID : 35945692
KEYWORDS : Animals|Humans|Mice|Brain|Brain Concussion|complications|Brain Injuries, Traumatic|complications|Disease Models, Animal|Neuroinflammatory Diseases|Positron-Emission Tomography|methods|Receptors, GABA
Show abstract [+]
Despite an apparently silent imaging, some patients with mild traumatic brain injury (TBI) experience cognitive dysfunctions, which may persist chronically. Brain changes responsible for these dysfunctions are unclear and commonly overlooked. It is thus crucial to increase our understanding of the mechanisms linking the initial event to the functional deficits, and to provide objective evidence of brain tissue alterations underpinning these deficits. We first set up a murine model of closed-head controlled cortical impact, which provoked persistent cognitive and sensorimotor deficits, despite no evidence of brain contusion or bleeding on MRI, thus recapitulating features of mild TBI. Molecular MRI for P-selectin, a key adhesion molecule, detected no sign of cerebrovascular inflammation after mild TBI, as confirmed by immunostainings. By contrast, in vivo PET imaging with the TSPO ligand [18F]DPA-714 demonstrated persisting signs of neuroinflammation in the ipsilateral cortex and hippocampus after mild TBI. Interestingly, immunohistochemical analyses confirmed these spatio-temporal profiles, showing a robust parenchymal astrogliosis and microgliosis, at least up to 3 weeks post-injury in both the cortex and hippocampus. In conclusion, we show that even one single mild TBI induces long-term behavioural deficits, associated with a persistent neuro-inflammatory status that can be detected by PET imaging.
Tracking the immune response by MRI using biodegradable and ultrasensitive microprobes.
Martinez de Lizarrondo S, Jacqmarcq C, Naveau M, Navarro-Oviedo M, Pedron S, Adam A, Freis B, Allouche S, Goux D, Razafindrakoto S, Gazeau F, Mertz D, Vivien D, Bonnard T, Gauberti M
Sci Adv 2375-2548
PMID : 35857494
Show abstract [+]
Molecular magnetic resonance imaging (MRI) holds great promise for diagnosis and therapeutic monitoring in a wide range of diseases. However, the low intrinsic sensitivity of MRI to detect exogenous contrast agents and the lack of biodegradable microprobes have prevented its clinical development. Here, we synthetized a contrast agent for molecular MRI based on a previously unknown mechanism of self-assembly of catechol-coated magnetite nanocrystals into microsized matrix-based particles. The resulting biodegradable microprobes (M3P for microsized matrix-based magnetic particles) carry up to 40,000 times higher amounts of superparamagnetic material than classically used nanoparticles while preserving favorable biocompatibility and excellent water dispersibility. After conjugation to monoclonal antibodies, targeted M3P display high sensitivity and specificity to detect inflammation in vivo in the brain, kidneys, and intestinal mucosa. The high payload of superparamagnetic material, excellent toxicity profile, short circulation half-life, and widespread reactivity of the M3P particles provides a promising platform for clinical translation of immuno-MRI.
Relationships between diabetes-related vascular risk factors and neurodegeneration biomarkers in healthy aging and Alzheimer's disease.
Palix C, Felisatti F, Gonneaud J, Kuhn E, Mézenge F, Landeau B, Chocat A, Quillard A, Egret S, Delarue M, Sayette V, Vivien D, Chételat G, Poisnel G
Neurobiol Aging 1558-1497
PMID : 35843110
KEYWORDS : Aged|Alzheimer Disease|complications|Amyloid beta-Peptides|Atrophy|complications|Biomarkers|Cognitive Dysfunction|complications|Diabetes Mellitus, Type 2|complications|Healthy Aging|Humans|Magnetic Resonance Imaging|Positron-Emission Tomography|methods|Risk Factors
Show abstract [+]
Vascular risk factors such as hyperglycemia and platelet hyperactivation play a significant role in type 2 diabetes (T2D), a risk factor for AD. We investigated the relationships between glycemia levels, platelet indices (platelet count; mean platelet volume (MPV)) and AD neuroimaging markers in 105 cognitively unimpaired adults, including 21 amyloid-negative older adults (Aβ-neg controls), and 45 amyloid-positive patients with mild cognitive impairment or dementia (Aβ-pos patients). We assessed between-group differences on the two T2D-related vascular risk factors, then the association between blood parameters and multimodal neuroimaging (structural MRI, 18F-fluorodeoxyglucose, and 18F-florbetapir-PET) in cognitively unimpaired adults and Aβ-pos patients using multiple regressions. Compared to Aβ-neg controls, Aβ-pos patients showed lower platelet count and higher MPV. In cognitively unimpaired adults, increased glycemia levels were associated with atrophy and hypometabolism in AD-sensitive regions. In Aβ-pos patients, increased MPV was associated with entorhinal and perirhinal cortex atrophy. Subclinical but high glycemia levels in healthy individuals and MPV in AD patients are associated with neurodegeneration in AD-sensitive brain regions but not with amyloid deposition.
Depressive Symptoms Have Distinct Relationships With Neuroimaging Biomarkers Across the Alzheimer's Clinical Continuum.
Moulinet I, Touron E, Mézenge F, Dautricourt S, De La Sayette V, Vivien D, Marchant NL, Poisnel G, Chételat G
Front Aging Neurosci 1663-4365
PMID : 35795235
Show abstract [+]
Depressive and anxiety symptoms are frequent in Alzheimer's disease and associated with increased risk of developing Alzheimer's disease in older adults. We sought to examine their relationships to Alzheimer's disease biomarkers across the preclinical and clinical stages of the disease.
In utero alcohol exposure impairs vessel-associated positioning and differentiation of oligodendrocytes in the developing neocortex.
Brosolo M, Lecointre M, Laquerrière A, Janin F, Genty D, Lebon A, Lesueur C, Vivien D, Marret S, Marguet F, Gonzalez BJ
Neurobiol Dis 1095-953X
PMID : 35760273
KEYWORDS : Animals|Ethanol|Female|Fetal Alcohol Spectrum Disorders|pathology|Humans|Mice|Neocortex|metabolism|Oligodendroglia|metabolism|Pregnancy|Prenatal Exposure Delayed Effects|metabolism
Show abstract [+]
Prenatal alcohol exposure (PAE) is a major cause of nongenetic mental retardation and can lead to fetal alcohol syndrome (FAS), the most severe manifestation of fetal alcohol spectrum disorder (FASD). FASD infants present behavioral disabilities resulting from neurodevelopmental defects. Both grey and white matter lesions have been characterized and are associated with apoptotic death and/or ectopic migration profiles. In the last decade, it was shown that PAE impairs brain angiogenesis, and the radial organization of cortical microvessels is lost. Concurrently, several studies have reported that tangential migration of oligodendrocyte precursors (OPCs) originating from ganglionic eminences is vascular associated. Because numerous migrating oligodendrocytes enter the developing neocortex, the present study aimed to determine whether migrating OPCs interacted with radial cortical microvessels and whether alcohol-induced vascular impairments were associated with altered positioning and differentiation of cortical oligodendrocytes. Using a 3D morphometric analysis, the results revealed that in both human and mouse cortices, 15 to 40% of Olig2-positive cells were in close association with radial cortical microvessels, respectively. Despite perinatal vascular disorganization, PAE did not modify the vessel association of Olig2-positive cells but impaired their positioning between deep and superficial cortical layers. At the molecular level, PAE markedly but transiently reduced the expression of CNPase and MBP, two differentiation markers of immature and mature oligodendrocytes. In particular, PAE inverted their distribution profiles in cortical layers V and VI and reduced the thickness of the myelin sheath of efferent axons. These perinatal oligo-vascular defects were associated with motor disabilities that persisted in adults. Altogether, the present study provides the first evidence that Olig2-positive cells entering the neocortex are associated with radial microvessels. PAE disorganized the cortical microvasculature and delayed the positioning and differentiation of oligodendrocytes. Although most of these oligovascular defects occurred in perinatal life, the offspring developed long-term motor troubles. Altogether, these data suggest that alcohol-induced oligo-vascular impairments contribute to the neurodevelopmental issues described in FASD.
Plasma Levels of Tissue-Type Plasminogen Activator (tPA) in Normal Aging and Alzheimer's Disease: Links With Cognition, Brain Structure, Brain Function and Amyloid Burden.
Tomadesso C, de Lizarrondo SM, Ali C, Landeau B, Mézenge F, Perrotin A, de La Sayette V, Vivien D, Chételat G
Front Aging Neurosci 1663-4365
PMID : 35747448
Show abstract [+]
Tissue-type plasminogen activator (tPA) is a protease known for its fibrinolytic action but is also involved in physiological and pathophysiological aging processes; including amyloid elimination and synaptic plasticity. The aim of the study was to investigate the role of tPA in cognitive and brain aging. Therefore, we assessed the links between tPA plasma concentration and cognition, structural MRI, FDG-PET and Flobetapir-PET neuroimaging in 155 cognitively unimpaired adults (CUA, aged 20-85 years old) and 32 patients with Alzheimer's disease (ALZ). A positive correlation was found between tPA and age in CUA (p < 0.001), with males showing higher tPA than females (p = 0.05). No significant difference was found between ALZ patients and cognitively unimpaired elders (CUE). Plasma tPA in CUA negatively correlated with global brain volume. No correlation was found with brain FDG metabolism or amyloid deposition. Age-related tPA changes were associated to changes in blood pressure, glycemia and body mass index. Within the ALZ patients, tPA didn't correlate with any cognitive or neuroimaging measures, but only with physiological measures. Altogether our study suggests that increased tPA plasma concentration with age is related to neuronal alterations and cardiovascular risk factors.
PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models.
Lebas H, Guérit S, Picot A, Boulay AC, Fournier A, Vivien D, Cohen Salmon M, Docagne F, Bardou I
Cell Mol Life Sci 1420-9071
PMID : 35633384
KEYWORDS : Animals|Astrocytes|metabolism|Central Nervous System|metabolism|Disease Models, Animal|Encephalomyelitis, Autoimmune, Experimental|genetics|Fibrin|In Situ Hybridization, Fluorescence|Mice|Mice, Knockout|Multiple Sclerosis|genetics|Plasminogen Activator Inhibitor 1|genetics|Serpin E2
Show abstract [+]
In multiple sclerosis (MS), disturbance of the plasminogen activation system (PAS) and blood brain barrier (BBB) disruption are physiopathological processes that might lead to an abnormal fibrin(ogen) extravasation into the parenchyma. Fibrin(ogen) deposits, usually degraded by the PAS, promote an autoimmune response and subsequent demyelination. However, the PAS disruption is not well understood and not fully characterized in this disorder.
Dynamic functional connectivity patterns associated with dementia risk.
Dautricourt S, Gonneaud J, Landeau B, Calhoun VD, de Flores R, Poisnel G, Bougacha S, Ourry V, Touron E, Kuhn E, Demintz-King H, Marchant NL, Vivien D, de la Sayette V, Lutz A, Chételat G,
Alzheimers Res Ther 1758-9193
PMID : 35606867
KEYWORDS : Aged|Brain|diagnostic imaging|Brain Mapping|Cholesterol, LDL|Dementia|diagnostic imaging|Humans|Magnetic Resonance Imaging
Show abstract [+]
This study assesses the relationships between dynamic functional network connectivity (DFNC) and dementia risk.
Role of Cardiovascular Risk Factors on the Association Between Physical Activity and Brain Integrity Markers in Older Adults.
Felisatti F, Gonneaud J, Palix C, Garnier-Crussard A, Mézenge F, Landeau B, Chocat A, Quillard A, Ferrand-Devouge E, de La Sayette V, Vivien D, Chételat G, Poisnel G,
Neurology 1526-632X
PMID : 35418459
KEYWORDS : Aged|Biomarkers|metabolism|Brain|diagnostic imaging|Cardiovascular Diseases|diagnostic imaging|Cholesterol|metabolism|Exercise|Glucose|metabolism|Heart Disease Risk Factors|Humans|Insulins|metabolism|Magnetic Resonance Imaging|Risk Factors
Show abstract [+]
Physical activity has been associated with a decreased risk for dementia, but the mechanisms underlying this association remain to be determined. Our objective was to assess whether cardiovascular risk factors mediate the association between physical activity and brain integrity markers in older adults.
Men and women show partly distinct effects of physical activity on brain integrity.
Gonneaud J, Moreau I, Felisatti F, Arenaza-Urquijo E, Ourry V, Touron E, de la Sayette V, Vivien D, Chételat G
Alzheimers Dement (Amst) 2352-8729
PMID : 35382233
Show abstract [+]
Physical inactivity and female sex are independently associated with increased Alzheimer's disease (AD) lifetime risk. This study investigates the possible interactions between sex and physical activity on neuroimaging biomarkers.
tPA-NMDAR Signaling Blockade Reduces the Incidence of Intracerebral Aneurysms.
Louet ER, Glavan M, Orset C, Parcq J, Hanley DF, Vivien D
Transl Stroke Res 1868-601X
PMID : 35307812
KEYWORDS : Mice|Animals|Tissue Plasminogen Activator|therapeutic use|Receptors, N-Methyl-D-Aspartate|metabolism|N-Methylaspartate|Incidence|Intracranial Aneurysm|drug therapy|Antibodies, Monoclonal|metabolism|Aneurysm, Ruptured|complications
Show abstract [+]
Intracranial aneurysms (IAs) are pathological dilatations affecting cerebral arteries, and their ruptures lead to devasting intracranial hemorrhages. Although the mechanisms underlying the IA formation and rupture are still unclear, some factors have been identified as critical in the control of the vascular remodeling pathways associated with aneurysms. In a preclinical model, we have previously proposed the implication of the vascular serine protease, the tissue-type plasminogen activator (tPA), as one of the key players in this pathology. Here, we provide insights into the mechanism by which tPA is implicated in the formation and rupture of aneurysms. This was addressed using a murine model of IAs combined with (i) hydrodynamic transfections of various tPA mutants based on the potential implications of the different tPA domains in this pathophysiology and (ii) a pharmacological approach using a monoclonal antibody targeting tPA-dependent NMDA receptor (NMDAR) signaling and in vivo magnetic resonance brain imaging (MRI). Our results show that the endovascular tPA-NMDAR axis is implicated in IA formation and possibly their rupture. Accordingly, the use of a monoclonal antibody designed to block tPA-dependent endothelial NMDAR signaling (Glunomab®) decreases the rate of intracranial aneurysm formation and their rupture. The present study gives new insights into the IA pathophysiology by demonstrating the implication of the tPA-dependent endothelial NMDAR signaling. In addition, the present data proposes that a monoclonal antibody injected intravenously to target this process, i.e., Glunomab® could be a useful therapeutic candidate for this devastating disease.
PKCδ-positive GABAergic neurons in the central amygdala exhibit tissue-type plasminogen activator: role in the control of anxiety.
Douceau S, Lemarchand E, Hommet Y, Lebouvier L, Joséphine C, Bemelmans AP, Maubert E, Agin V, Vivien D
Mol Psychiatry 1476-5578
PMID : 35145231
KEYWORDS : Animals|Anxiety|Anxiety Disorders|Central Amygdaloid Nucleus|metabolism|GABAergic Neurons|metabolism|Mice|Mice, Inbred C57BL|Protein Kinase C-delta|metabolism|Tissue Plasminogen Activator|genetics
Show abstract [+]
Tissue plasminogen activator (tPA) is a serine protease expressed in several brain regions and reported to be involved in the control of emotional and cognitive functions. Nevertheless, little is known about the structure-function relationships of these tPA-dependent behaviors. Here, by using a new model of constitutive tPA-deficient mice (tPAnull), we first show that tPA controls locomotor activity, spatial cognition and anxiety. To investigate the brain structures involved in these tPA-dependent behavioral phenotypes, we next generated tPAflox mice allowing conditional tPA deletion (cKO) following stereotaxic injections of adeno-associated virus driving Cre-recombinase expression (AAV-Cre-GFP). We demonstrate that tPA removal in the dentate gyrus of the hippocampus induces hyperactivity and partial spatial memory deficits. Moreover, the deletion of tPA in the central nucleus of the amygdala, but not in the basolateral nucleus, induces hyperactivity and reduced anxiety-like level. Importantly, we prove that these behaviors depend on the tPA present in the adult brain and not on neurodevelopmental disorders. Also, interestingly, our data show that tPA from Protein kinase-C delta-positive (PKCδ) GABAergic interneurons of the lateral/ capsular part of adult mouse central amygdala controls emotional functions through neuronal activation of the medial central amygdala. Together, our study brings new data about the critical central role of tPA in behavioral modulations in adult mice.
Bumetanide lowers acute hydrocephalus in a rat model of subarachnoid hemorrhage.
Metayer T, Orset C, Ali C, Furon J, Szabla N, Emery E, Vivien D, Gaberel T
Acta Neurochir (Wien) 0942-0940
PMID : 35094147
KEYWORDS : Animals|Bumetanide|pharmacology|Choroid Plexus|Hydrocephalus|drug therapy|Rats|Rats, Wistar|Subarachnoid Hemorrhage|complications
Show abstract [+]
Subarachnoid hemorrhage (SAH) can lead to acute hydrocephalus (AH). AH pathophysiology is classically attributed to an obstruction of the arachnoid granulations by blood. Recent findings in rodents suggest that after intraventricular hemorrhage, AH is related to cerebrospinal fluid (CSF) hypersecretion by the choroid plexus (CP), as it can be reduced by intracerebroventricular (ICV) injection of bumetanide.
Roles of the tissue-type plasminogen activator in immune response.
Seillier C, Hélie P, Petit G, Vivien D, Clemente D, Le Mauff B, Docagne F, Toutirais O
Cell Immunol 1090-2163
PMID : 34781155
KEYWORDS : Antigen-Presenting Cells|immunology|Blood Coagulation|immunology|COVID-19|epidemiology|Endothelial Cells|immunology|Fibrinolysis|immunology|Humans|Immunity|immunology|Models, Immunological|Pandemics|SARS-CoV-2|immunology|T-Lymphocytes|immunology|Tissue Plasminogen Activator|immunology
Show abstract [+]
The COVID-19 pandemic has once again brought to the forefront the existence of a tight link between the coagulation/fibrinolytic system and the immunologic processes. Tissue-type plasminogen activator (tPA) is a serine protease with a key role in fibrinolysis by converting plasminogen into plasmin that can finally degrade fibrin clots. tPA is released in the blood by endothelial cells and hepatocytes but is also produced by various types of immune cells including T cells and monocytes. Beyond its role on hemostasis, tPA is also a potent modulator of inflammation and is involved in the regulation of several inflammatory diseases. Here, after a brief description of tPA structure, we review its new functions in adaptive immunity focusing on T cells and antigen presenting cells. We intend to synthesize the recent knowledge on proteolysis- and receptor-mediated effects of tPA on immune response in physiological and pathological context.
An updated model of hydrocephalus in sheep to evaluate the performance of a device for ambulatory wireless monitoring of cerebral pressure through shunts.
Perrotte M, Lazardeux J, Sistiaga PP, Chazalviel L, Saulnier R, Metayer T, Isnard C, Emery E, Auvray P, Vivien D, Gaberel T
Neurochirurgie 1773-0619
PMID : 34774581
KEYWORDS : Animals|Brain|surgery|Cerebrospinal Fluid Shunts|methods|Humans|Hydrocephalus|complications|Kaolin|Monitoring, Ambulatory|Sheep|Ventriculoperitoneal Shunt
Show abstract [+]
Cerebrospinal fluid (CSF) diversion by shunts is the most common surgical treatment for hydrocephalus. Though effective, shunts are associated with risk of dysfunction leading to multiple surgical revisions, affecting patient quality-of-life and incurring high healthcare costs. There is a need for ambulatory monitoring systems for life-long assessment of shunt status. The present study aimed to develop a preclinical model assessing the feasibility of our wireless device for continuous monitoring of cerebral pressure in shunts.
Sex-specificities in anxiety and depressive symptoms across the lifespan and their links with multimodal neuroimaging.
Moulinet I, Landeau B, Touron E, De La Sayette V, Desgranges B, Vivien D, Marchant N, Poisnel G, Chételat G
J Affect Disord 1573-2517
PMID : 34637806
KEYWORDS : Adult|Alzheimer Disease|Anxiety|diagnostic imaging|Brain|diagnostic imaging|Depression|diagnostic imaging|Female|Humans|Longevity|Magnetic Resonance Imaging|Male|Neuroimaging|Positron-Emission Tomography
Show abstract [+]
Anxiety and depressive symptoms are associated with impaired well-being, higher risk of developing psychoaffective disorders and are risk factors for Alzheimer's disease (AD). To further understand their relevance and the mechanisms underlying their link with AD, our aims were to assess how anxiety and depressive symptoms changed with age and related to AD neuroimaging biomarkers across the adult lifespan, while also exploring sex specificities.
Post-acute delivery of α5-GABAA antagonist, S 44819, improves functional recovery in juvenile rats following stroke.
Lebrun F, Violle N, Letourneur A, Muller C, Fischer N, Levilly A, Orset C, Sors A, Vivien D
Exp Neurol 1090-2430
PMID : 34597681
KEYWORDS : Animals|Benzodiazepines|pharmacology|GABA-A Receptor Antagonists|pharmacology|Male|Oxazoles|pharmacology|Rats|Rats, Sprague-Dawley|Recovery of Function|drug effects|Stroke|physiopathology
Show abstract [+]
Hypo-excitability was reported in the peri-infarct tissue following stroke, an effect counteracted by a blockage of α5-GABAA receptors in adult rodents. Our present study aims to evaluate the effect of a selective α5-GABAA receptor antagonist, S 44819, in stroke in juvenile animals. We have set up and characterized an original model of transient ischemic stroke in 28 day-old Sprague-Dawley rats (45-min occlusion of the middle cerebral artery by intraluminal suture). In this model, S 44819 (1, 3 and 10 mg/kg, b.i.d) was orally administered from day 3 to day 16 after stroke onset. Sensorimotor recovery was assessed on day 1, day 9 and day 16 after stroke onset. Results show that rats treated with S 44819 at the doses of 3 and 10 mg/kg displayed a significant improvement of the neurological deficits (neuroscore) on day 9 and day 16, when compared with animals treated with vehicle. Grip-test data analysis reveals that rats treated with S 44819 at the dose of 3 mg/kg displayed a better recovery on day 9 and day 16. These results are in agreement with those previously observed in adult rats, demonstrating that targeting α5-GABAA receptors improves neurological recovery after stroke in juvenile rats.
Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia.
Thiebaut AM, Buendia I, Ginet V, Lemarchand E, Boudjadja MB, Hommet Y, Lebouvier L, Lechevallier C, Maillasson M, Hedou E, Déglon N, Oury F, Rubio M, Montaner J, Puyal J, Vivien D, Roussel BD
Autophagy 1554-8635
PMID : 34520334
KEYWORDS : Autophagy|Brain Ischemia|drug therapy|Glucose|pharmacology|Humans|Hypoxia|Insulin-Like Growth Factor Binding Protein 3|metabolism|Insulin-Like Growth Factor I|metabolism|Mechanistic Target of Rapamycin Complex 1|metabolism|Oxygen|pharmacology|Phosphatidylinositol 3-Kinases|metabolism|Proto-Oncogene Proteins c-akt|metabolism|Signal Transduction|Stroke|drug therapy|TOR Serine-Threonine Kinases|metabolism|Thrombolytic Therapy|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death. In two in vitro models of hypoxia reperfusion and an in vivo model of thromboembolic stroke with thrombolysis by PLAT/tPA, we found that ischemia enhances neuronal deleterious autophagy. Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both in vitro and in vivo. We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed in vitro, in vivo and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation. AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGDreox: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin.
Retreatment of previously treated intracranial aneurysm: Procedural complications and risk factors for complications.
Metayer T, Lechanoine F, Bougaci N, de Schlichting E, Terrier L, Derrey S, Barbier C, Papagiannaki C, Ashraf A, Tahon F, Leplus A, Gay E, Emery E, Briant AR, Vivien D, Gaberel T
Neurochirurgie 1773-0619
PMID : 34487752
KEYWORDS : Aneurysm, Ruptured|therapy|Embolization, Therapeutic|Endovascular Procedures|adverse effects|Humans|Intracranial Aneurysm|surgery|Recurrence|Retreatment|Retrospective Studies|Risk Factors|Treatment Outcome
Show abstract [+]
Intracranial aneurysm (IA) is a frequent vascular malformation that can be managed by endovascular treatment (EVT) or microsurgery. A previously treated IA can recanalize, which may require further treatment. The aim of our study was to evaluate procedural complications related to IA retreatment and their risk factors.
White matter hyperintensity topography in Alzheimer's disease and links to cognition.
Garnier-Crussard A, Bougacha S, Wirth M, Dautricourt S, Sherif S, Landeau B, Gonneaud J, De Flores R, de la Sayette V, Vivien D, Krolak-Salmon P, Chételat G
Alzheimers Dement 1552-5279
PMID : 34322985
KEYWORDS : Alzheimer Disease|pathology|Amyloid beta-Peptides|Atrophy|pathology|Cognition|Cross-Sectional Studies|Humans|Magnetic Resonance Imaging|White Matter|diagnostic imaging
Show abstract [+]
White matter hyperintensities (WMH) are often described in Alzheimer's disease (AD), but their topography and specific relationships with cognition remain unclear.
2021
Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival.
Hedou E, Douceau S, Chevilley A, Varangot A, Thiebaut AM, Triniac H, Bardou I, Ali C, Maillasson M, Crepaldi T, Comoglio P, Lemarchand E, Agin V, Roussel BD, Vivien D
Int J Mol Sci 1422-0067
PMID : 34948279
KEYWORDS : Animals|Cell Death|drug effects|Cell Survival|drug effects|Fetus|Mice|Neurons|metabolism|Primary Cell Culture|Protein Isoforms|Proto-Oncogene Proteins c-met|metabolism|Receptor Cross-Talk|physiology|Receptors, N-Methyl-D-Aspartate|metabolism|Signal Transduction|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the recruitment of N-Methyl-d-Aspartate receptors (NMDARs) and to the endocytosis and proteasome-dependent degradation of NMDARs containing the GluN2B subunit. Accordingly, tc-tPA down-regulated GluN2B-NMDAR-driven signalling, a process prevented by blockers of HGFR/MET and mimicked by its agonists, leading to a modulation of neuronal death. Thus, our present study unmasks a new mechanism of action of tPA, with its two-chains form mediating a crosstalk between MET and the GluN2B subunit of NMDARs to control neuronal survival.
Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Is There a Relevant Experimental Model? A Systematic Review of Preclinical Literature.
Goursaud S, Martinez de Lizarrondo S, Grolleau F, Chagnot A, Agin V, Maubert E, Gauberti M, Vivien D, Ali C, Gakuba C
Front Cardiovasc Med 2297-055X
PMID : 34869659
Show abstract [+]
Delayed cerebral ischemia (DCI) is one of the main prognosis factors for disability after aneurysmal subarachnoid hemorrhage (SAH). The lack of a consensual definition for DCI had limited investigation and care in human until 2010, when a multidisciplinary research expert group proposed to define DCI as the occurrence of cerebral infarction (identified on imaging or histology) associated with clinical deterioration. We performed a systematic review to assess whether preclinical models of SAH meet this definition, focusing on the combination of noninvasive imaging and neurological deficits. To this aim, we searched in PUBMED database and included all rodent SAH models that considered cerebral ischemia and/or neurological outcome and/or vasospasm. Seventy-eight publications were included. Eight different methods were performed to induce SAH, with blood injection in the cisterna magna being the most widely used (n = 39, 50%). Vasospasm was the most investigated SAH-related complication (n = 52, 67%) compared to cerebral ischemia (n = 30, 38%), which was never investigated with imaging. Neurological deficits were also explored (n = 19, 24%). This systematic review shows that no preclinical SAH model meets the 2010 clinical definition of DCI, highlighting the inconsistencies between preclinical and clinical standards. In order to enhance research and favor translation to humans, pertinent SAH animal models reproducing DCI are urgently needed.
Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit.
Gilbert A, Elorza-Vidal X, Rancillac A, Chagnot A, Yetim M, Hingot V, Deffieux T, Boulay AC, Alvear-Perez R, Cisternino S, Martin S, Taïb S, Gelot A, Mignon V, Favier M, Brunet I, Declèves X, Tanter M, Estevez R, Vivien D, Saubaméa B, Cohen-Salmon M
Elife 2050-084X
PMID : 34723793
KEYWORDS : Animals|Cell Adhesion Molecules, Neuron-Glia|genetics|Cysts|genetics|Disease Models, Animal|Hereditary Central Nervous System Demyelinating Diseases|genetics|Membrane Proteins|genetics|Mice|Mice, Knockout|Nerve Tissue Proteins|genetics
Show abstract [+]
Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare type of leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes. Perivascular astrocytic processes along with blood vessels form the gliovascular unit. It was not previously known how MLC1 influences the physiology of the gliovascular unit. Here, using the Mlc1 knock-out mouse model of MLC, we demonstrated that MLC1 controls the postnatal development and organization of perivascular astrocytic processes, vascular smooth muscle cell contractility, neurovascular coupling, and intraparenchymal interstitial fluid clearance. Our data suggest that MLC is a developmental disorder of the gliovascular unit, and perivascular astrocytic processes and vascular smooth muscle cell maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.
Harmonisation and Between-Country Differences of the Lifetime of Experiences Questionnaire in Older Adults.
Ourry V, Marchant NL, Schild AK, Coll-Padros N, Klimecki OM, Krolak-Salmon P, Goldet K, Reyrolle L, Bachelet R, Sannemann L, Meiberth D, Demnitz-King H, Whitfield T, Botton M, Lebahar J, Gonneaud J, de Flores R, Molinuevo JL, Jessen F, Vivien D, de la Sayette V, Valenzuela MJ, Rauchs G, Wirth M, Chételat G, Arenaza-Urquijo EM,
Front Aging Neurosci 1663-4365
PMID : 34720992
Show abstract [+]
The Lifetime of Experiences Questionnaire (LEQ) assesses complex mental activity across the life-course and has been associated with brain and cognitive health. The different education systems and occupation classifications across countries represent a challenge for international comparisons. The objectives of this study were four-fold: to adapt and harmonise the LEQ across four European countries, assess its validity across countries, explore its association with brain and cognition and begin to investigate between-country differences in life-course mental activities. The LEQ was administered to 359 cognitively unimpaired older adults (mean age and education: 71.2, 13.2 years) from IMAP and EU-funded Medit-Ageing projects. Education systems, classification of occupations and scoring guidelines were adapted to allow comparisons between France, Germany, Spain and United Kingdom. We assessed the LEQ's (i) concurrent validity with a similar instrument (cognitive activities questionnaire - CAQ) and its structural validity by testing the factors' structure across countries, (ii) we investigated its association with cognition and neuroimaging, and (iii) compared its scores between countries. The LEQ showed moderate to strong positive associations with the CAQ and revealed a stable multidimensional structure across countries that was similar to the original LEQ. The LEQ was positively associated with global cognition. Between-country differences were observed in leisure activities across the life-course. The LEQ is a promising tool for assessing the multidimensional construct of cognitive reserve and can be used to measure socio-behavioural determinants of cognitive reserve in older adults across countries. Longitudinal studies are warranted to test further its clinical utility.
Subjective cognitive decline: opposite links to neurodegeneration across the Alzheimer's continuum.
Kuhn E, Perrotin A, Tomadesso C, André C, Sherif S, Bejanin A, Touron E, Landeau B, Mezenge F, Vivien D, De La Sayette V, Chételat G,
Brain Commun 2632-1297
PMID : 34704027
Show abstract [+]
Subjective memory decline is associated with neurodegeneration and increased risk of cognitive decline in participants with no or subjective cognitive impairment, while in patients with mild cognitive impairment or Alzheimer's-type dementia, findings are inconsistent. Our aim was to provide a comprehensive overview of subjective memory decline changes, relative to objective memory performances, and of their relationships with neurodegeneration, across the clinical continuum of Alzheimer's disease. Two hundred participants from the Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce (IMAP+) primary cohort and 731 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) replication cohort were included. They were divided into four clinical groups (Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce/Alzheimer's Disease Neuroimaging Initiative): controls (n = 67/147, age: 60-84/60-90, female: 54/55%), patients with subjective cognitive decline (n = 30/84, age: 54-84/65-80, female: 44/63%), mild cognitive impairment (n = 50/369, age: 58-86/55-88, female: 45/44%) or Alzheimer's-type dementia (n = 36/121, age: 51-86/61-90, female: 41/41%). Subjective and objective memory scores, and their difference (i.e. delta score reflecting memory awareness), were compared between groups. Then, voxelwise relationships between subjective memory decline and neuroimaging measures of neurodegeneration [atrophy (T1-MRI) and hypometabolism (18F-fluorodeoxyglucose-PET)] were assessed across clinical groups and the interactive effect of the level of cognitive impairment within the entire sample was assessed. Analyses were adjusted for age, sex and education, and repeated including only the amyloid-positive participants. In Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce, the level of subjective memory decline was higher in all patient groups (all P < 0.001) relative to controls, but similar between patient groups. In contrast, objective memory deficits progressively worsened from the subjective cognitive decline to the dementia group (all P < 0.001). Accordingly, the delta score showed a progressive decline in memory awareness across clinical groups (all P < 0.001). Voxelwise analyses revealed opposite relationships between the subjective memory decline score and neurodegeneration across the clinical continuum. In the earliest stages (i.e. patients with subjective cognitive decline or Mini Mental State Examination > 28), greater subjective memory decline was associated with increased neurodegeneration, while in later stages (i.e. patients with mild cognitive impairment, dementia or Mini Mental State Examination < 27) a lower score was related to more neurodegeneration. Similar findings were recovered in the Alzheimer's Disease Neuroimaging Initiative replication cohort, with slight differences according to the clinical group, and in the amyloid-positive subsamples. Altogether, our findings suggest that the subjective memory decline score should be interpreted differently from normal cognition to dementia. Higher scores might reflect greater neurodegeneration in earliest stages, while in more advanced stages lower scores might reflect decreased memory awareness, i.e. more anosognosia associated with advanced neurodegeneration.
Molecular Magnetic Resonance Imaging of Vascular Inflammation After Recanalization in a Rat Ischemic Stroke Model.
Franx BAA, Van der Toorn A, Van Heijningen C, Vivien D, Bonnard T, Dijkhuizen RM
Stroke 1524-4628
PMID : 34674544
KEYWORDS : Animals|Disease Models, Animal|Endovascular Procedures|Infarction, Middle Cerebral Artery|pathology|Magnetic Resonance Imaging|methods|Male|Neuroinflammatory Diseases|pathology|Rats|Rats, Sprague-Dawley|Thrombectomy|Vasculitis|pathology
Show abstract [+]
Brain imaging has become central in the management of acute ischemic stroke. Detection of parenchymal injury and perfusion enables characterization of the extent of ischemic damage, which guides treatment decision-making. Additional assessment of secondary events, such as inflammation, which may particularly arise after recanalization, may improve diagnosis and (supplementary) treatment selection. Therefore, we developed and tested a molecular magnetic resonance imaging (MRI) approach for in vivo detection of vascular inflammation after transient middle cerebral artery occlusion in rats.
Making Visible the Invisible.
Vivien D
Neuroscience 1873-7544
PMID : 34583818
Fucoidan-functionalized polysaccharide submicroparticles loaded with alteplase for efficient targeted thrombolytic therapy.
Zenych A, Jacqmarcq C, Aid R, Fournier L, Forero Ramirez LM, Chaubet F, Bonnard T, Vivien D, Letourneur D, Chauvierre C
Biomaterials 1878-5905
PMID : 34482087
KEYWORDS : Animals|Endothelial Cells|Fibrinolysis|Fibrinolytic Agents|therapeutic use|Mice|Polysaccharides|therapeutic use|Stroke|drug therapy|Thrombolytic Therapy|Tissue Plasminogen Activator|therapeutic use
Show abstract [+]
Intravenous administration of fibrinolytic drugs is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and might trigger hemorrhagic transformations. Therefore, it is mandatory to develop innovative nanomedicine-based solutions for more efficient and safer thrombolysis with biocompatible and biodegradable thrombus-targeted nanocarrier. Herein, fucoidan-functionalized hydrogel polysaccharide submicroparticles with high biocompatibility are elaborated by the inverse miniemulsion/crosslinking method. They are loaded with the gold standard fibrinolytic - alteplase - to direct site-specific fibrinolysis due to nanomolar interactions between fucoidan and P-selectin overexpressed on activated platelets and endothelial cells in the thrombus area. The thrombus targeting properties of these particles are validated in a microfluidic assay containing recombinant P-selectin and activated platelets under arterial and venous blood shear rates as well as in vivo. The experiments on the murine model of acute thromboembolic ischemic stroke support this product's therapeutic efficacy, revealing a faster recanalization rate in the middle cerebral artery than with free alteplase, which reduces post-ischemic cerebral infarct lesions and blood-brain barrier permeability. Altogether, this proof-of-concept study demonstrates the potential of a biomaterial-based targeted nanomedicine for the precise treatment of acute thrombotic events, such as ischemic stroke.
Engineered extracellular vesicles as brain therapeutics.
Lino MM, Simões S, Tomatis F, Albino I, Barrera A, Vivien D, Sobrino T, Ferreira L
J Control Release 1873-4995
PMID : 34428481
KEYWORDS : Blood-Brain Barrier|Brain|Brain Diseases|drug therapy|Drug Delivery Systems|Extracellular Vesicles|Humans
Show abstract [+]
Extracellular vesicles (EVs) are communication channels between different cell types in the brain, between the brain and the periphery and vice-versa, playing a fundamental role in physiology and pathology. The evidence that EVs might be able to cross the blood-brain barrier (BBB) make them very promising candidates as nanocarriers to treat brain pathologies. EVs contain a cocktail of bioactive factors, yet their content and surface can be further engineered to enhance their biological activity, stability and targeting ability. Native and engineered EVs have been reported for the treatment of different brain pathologies, although issues related to their modest accumulation and limited local therapeutic effect in the brain still need to be addressed. In this review, we cover the therapeutic applications of native and bioengineered EVs for brain diseases. We also review recent data about the interaction between EVs and the BBB and discuss the challenges and opportunities in clinical translation of EVs as brain therapeutics.
Role of inflammation in alcohol-related brain abnormalities: a translational study.
Lanquetin A, Leclercq S, de Timary P, Segobin S, Naveau M, Coulbault L, Maccioni P, Lorrai I, Colombo G, Vivien D, Rubio M, Pitel AL
Brain Commun 2632-1297
PMID : 34396111
Show abstract [+]
Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver-brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an in vivo neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out ex vivo neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage.
Longitudinal Changes in Hippocampal Network Connectivity in Alzheimer's Disease.
Dautricourt S, de Flores R, Landeau B, Poisnel G, Vanhoutte M, Delcroix N, Eustache F, Vivien D, de la Sayette V, Chételat G
Ann Neurol 1531-8249
PMID : 34279043
KEYWORDS : Aged|Aged, 80 and over|Alzheimer Disease|diagnostic imaging|Cross-Sectional Studies|Female|Hippocampus|diagnostic imaging|Humans|Longitudinal Studies|Magnetic Resonance Imaging|trends|Male|Middle Aged|Nerve Net|diagnostic imaging|Positron Emission Tomography Computed Tomography|trends
Show abstract [+]
The hippocampus is connected to 2 distinct cortical brain networks, the posterior-medial and the anterior-temporal networks, involving different medial temporal lobe (MTL) subregions. The aim of this study was to assess the functional alterations of these 2 networks, their changes over time, and links to cognition in Alzheimer's disease.
HGF and MET: From Brain Development to Neurological Disorders.
Desole C, Gallo S, Vitacolonna A, Montarolo F, Bertolotto A, Vivien D, Comoglio P, Crepaldi T
Front Cell Dev Biol 2296-634X
PMID : 34179015
Show abstract [+]
Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, encoded by the MET cellular proto-oncogene, are expressed in the nervous system from pre-natal development to adult life, where they are involved in neuronal growth and survival. In this review, we highlight, beyond the neurotrophic action, novel roles of HGF-MET in synaptogenesis during post-natal brain development and the connection between deregulation of MET expression and developmental disorders such as autism spectrum disorder (ASD). On the pharmacology side, HGF-induced MET activation exerts beneficial neuroprotective effects also in adulthood, specifically in neurodegenerative disease, and in preclinical models of cerebral ischemia, spinal cord injuries, and neurological pathologies, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). HGF is a key factor preventing neuronal death and promoting survival through pro-angiogenic, anti-inflammatory, and immune-modulatory mechanisms. Recent evidence suggests that HGF acts on neural stem cells to enhance neuroregeneration. The possible therapeutic application of HGF and HGF mimetics for the treatment of neurological disorders is discussed.
Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke.
Orset C, Arkelius K, Anfray A, Warfvinge K, Vivien D, Ansar S
Sci Rep 2045-2322
PMID : 34099834
KEYWORDS : Animals|Butadienes|pharmacokinetics|Disease Models, Animal|Drug Discovery|Drug Therapy, Combination|Drug-Related Side Effects and Adverse Reactions|prevention & control|Hemorrhage|prevention & control|Humans|Ischemic Stroke|drug therapy|Male|Matrix Metalloproteinase 9|metabolism|Mice|Mitogen-Activated Protein Kinase Kinases|metabolism|Nitriles|pharmacokinetics|Signal Transduction|Tissue Plasminogen Activator|pharmacology|Treatment Outcome
Show abstract [+]
In acute ischemic stroke, the only FDA-approved drug; recombinant tissue plasminogen activator (rt-PA) is limited by restricted time-window due to an enhanced risk of hemorrhagic transformation which is thought to be caused by metalloproteinase (MMP). In experimental stroke inhibitors of the mitogen-activated protein kinase kinase extracellular signal-regulated kinase kinase (MEK) 1/2 pathways reduce the MMPs. This study evaluated whether a MEK1/2 inhibitor in combination with rt-PA can prevent the detrimental effects of delayed rt-PA therapy in stroke. Thromboembolic stroke was induced in C57 black/6J mice and the MEK1/2 inhibitor U0126 was administrated 3.5 h and rt-PA 4 h post stroke-onset. Treatment with rt-PA demonstrated enhanced MMP-9 protein levels and hemorrhagic transformation which was prevented when U0126 was given in conjunction with rt-PA. By blocking the MMP-9 with U0126 the safety of rt-PA administration was improved and demonstrates a promising adjuvant strategy to reduce the harmful effects of delayed rt-PA treatment in acute ischemic stroke.
New Approaches in Nanomedicine for Ischemic Stroke.
Correa-Paz C, da Silva-Candal A, Polo E, Parcq J, Vivien D, Maysinger D, Pelaz B, Campos F
Pharmaceutics 1999-4923
PMID : 34065179
Show abstract [+]
Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in developed countries. Therapeutic methods such as recanalization approaches, neuroprotective drugs, or recovery strategies have been widely developed to improve the patient's outcome; however, important limitations such as a narrow therapeutic window, the ability to reach brain targets, or drug side effects constitute some of the main aspects that limit the clinical applicability of the current treatments. Nanotechnology has emerged as a promising tool to overcome many of these drug limitations and improve the efficacy of treatments for neurological diseases such as stroke. The use of nanoparticles as a contrast agent or as drug carriers to a specific target are some of the most common approaches developed in nanomedicine for stroke. Throughout this review, we have summarized our experience of using nanotechnology tools for the study of stroke and the search for novel therapies.
Factor XII protects neurons from apoptosis by epidermal and hepatocyte growth factor receptor-dependent mechanisms.
Garnier E, Levard D, Ali C, Buendia I, Hommet Y, Gauberti M, Crepaldi T, Comoglio P, Rubio M, Vivien D, Docagne F, Martinez de Lizarrondo S
J Thromb Haemost 1538-7836
PMID : 34060720
KEYWORDS : Animals|Apoptosis|Blood Coagulation|Factor XII|Factor XIIa|Mice|Neurons|Proto-Oncogene Proteins c-met
Show abstract [+]
Factor XII (FXII) is a serine protease that participates in the intrinsic coagulation pathway. Several studies have shown that plasma FXII exerts a deleterious role in cerebral ischemia and traumatic brain injury by promoting thrombo-inflammation. Nevertheless, the impact of FXII on neuronal cell fate remains unknown.
PI3KC2β inactivation stabilizes VE-cadherin junctions and preserves vascular integrity.
Anquetil T, Solinhac R, Jaffre A, Chicanne G, Viaud J, Darcourt J, Orset C, Geuss E, Kleinschnitz C, Vanhaesebroeck B, Vivien D, Hnia K, Larrue V, Payrastre B, Gratacap MP
EMBO Rep 1469-3178
PMID : 33880878
KEYWORDS : Adherens Junctions|metabolism|Animals|Antigens, CD|metabolism|Cadherins|genetics|Capillary Permeability|Endothelial Cells|metabolism|Endothelium, Vascular|metabolism|Mice|Phosphatidylinositol 3-Kinases|genetics
Show abstract [+]
Endothelium protection is critical, because of the impact of vascular leakage and edema on pathological conditions such as brain ischemia. Whereas deficiency of class II phosphoinositide 3-kinase alpha (PI3KC2α) results in an increase in vascular permeability, we uncover a crucial role of the beta isoform (PI3KC2β) in the loss of endothelial barrier integrity following injury. Here, we studied the role of PI3KC2β in endothelial permeability and endosomal trafficking in vitro and in vivo in ischemic stroke. Mice with inactive PI3KC2β showed protection against vascular permeability, edema, cerebral infarction, and deleterious inflammatory response. Loss of PI3KC2β in human cerebral microvascular endothelial cells stabilized homotypic cell-cell junctions by increasing Rab11-dependent VE-cadherin recycling. These results identify PI3KC2β as a potential new therapeutic target to prevent aggravating lesions following ischemic stroke.
Thrombolytic strategies for ischemic stroke in the thrombectomy era.
Gauberti M, Martinez de Lizarrondo S, Vivien D
J Thromb Haemost 1538-7836
PMID : 33834615
KEYWORDS : Brain Ischemia|drug therapy|Fibrinolysis|Fibrinolytic Agents|therapeutic use|Humans|Ischemic Stroke|Stroke|diagnosis|Thrombectomy|Thrombolytic Therapy|Tissue Plasminogen Activator|therapeutic use|Treatment Outcome
Show abstract [+]
Twenty-five years ago, intravenous thrombolysis has revolutionized the care of patients with acute ischemic stroke. Since 2015, randomized clinical trials have demonstrated that mechanical thrombectomy improves functional outcome in stroke patients over intravenous thrombolysis alone. More recently, three randomized clinical trials have suggested that mechanical thrombectomy alone is noninferior to a combined strategy with both intravenous thrombolysis and mechanical thrombectomy. In the present review, we will present the last clinical and preclinical studies on the use of thrombolysis in stroke patients in the modern thrombectomy era. At the cost of a potential increased risk of hemorrhagic transformation, thrombolysis may promote arterial recanalization before thrombectomy, improve the rate of successful recanalization after thrombectomy, and restore microcirculation patency downstream of the main thrombus. Besides, new thrombolytic strategies targeting tissue-type plasminogen activator resistant thrombi are being developed, which could strengthen the beneficial effects of thrombolysis without carrying additional pro-hemorrhagic effects. For instance, tenecteplase has shown improved rate of recanalization compared with tissue-type plasminogen activator (alteplase). Beyond fibrinolysis, DNA- and von Willebrand factor-targeted thrombolytic strategies have shown promising results in experimental models of ischemic stroke. New combined strategies, improved thrombolytics, and dedicated clinical trials in selected patients are eagerly awaited to further improve functional outcome in stroke.
Neuroserpin Is Strongly Expressed in the Developing and Adult Mouse Neocortex but Its Absence Does Not Perturb Cortical Lamination and Synaptic Proteome.
Kement D, Reumann R, Schostak K, Voß H, Douceau S, Dottermusch M, Schweizer M, Schlüter H, Vivien D, Glatzel M, Galliciotti G
Front Neuroanat 1662-5129
PMID : 33708076
Show abstract [+]
Neuroserpin is a serine protease inhibitor that regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin is strongly expressed during nervous system development as well as during adulthood, when it is predominantly found in regions eliciting synaptic plasticity. In the hippocampus, neuroserpin regulates developmental neurogenesis, synaptic maturation and in adult mice it modulates synaptic plasticity and controls cognitive and social behavior. High expression levels of neuroserpin in the neocortex starting from prenatal stage and persisting during adulthood suggest an important role for the serpin in the formation of this brain region and in the maintenance of cortical functions. In order to uncover neuroserpin function in the murine neocortex, in this work we performed a comprehensive investigation of its expression pattern during development and in the adulthood. Moreover, we assessed the role of neuroserpin in cortex formation by comparing cortical lamination and neuronal maturation between neuroserpin-deficient and control mice. Finally, we evaluated a possible regulatory role of neuroserpin at cortical synapses in neuroserpin-deficient mice. We observed that neuroserpin is expressed starting from the beginning of corticogenesis until adulthood throughout the neocortex in several classes of glutamatergic projection neurons and GABA-ergic interneurons. However, in the absence of neuroserpin we did not detect any alteration either in cortical layer formation, or in neuronal soma size and dendritic length. Furthermore, no significant quantitative changes were observed in the proteome of cortical synapses upon neuroserpin deficiency. We conclude that, although strongly expressed in the neocortex, absence of neuroserpin does not lead to gross developmental abnormalities, and does not perturb the composition of the cortical synaptic proteome.
Preventing the Long-term Effects of General Anesthesia on the Developing Brain: How Translational Research can Contribute.
Salaün JP, Poirel N, Dahmani S, Chagnot A, Gakuba C, Ali C, Gérard JL, Hanouz JL, Orliaguet G, Vivien D
Neuroscience 1873-7544
PMID : 33675916
KEYWORDS : Anesthesia, General|adverse effects|Anesthetics|Brain|Child|Humans|Neurotoxicity Syndromes|Translational Research, Biomedical
Show abstract [+]
In 2017, the Food and Drug Administration published a safety recommendation to limit the exposure to general anesthesia as much as possible below the age of three. Indeed, several preclinical and clinical studies have questioned the possible toxicity of general anesthesia on the developing brain. Since then, recent clinical studies tried to mitigate this alarming issue. What is true, what is false? Contrary to some perceptions, the debate is not over yet. Only stronger translational research will allow scientists to provide concrete answers to this public health issue. In this review, we will provide and discuss the more recent data in this field, including the point of view of preclinical researchers, neuropsychologists and pediatric anesthesiologists. Through translational research, preclinical researchers have more than ever a role to play to better understand and identify long-term effects of general anesthesia for pediatric surgery on brain development in order to minimize it.
Blood Biomarkers to Differentiate Ischemic and Hemorrhagic Strokes.
Bustamante A, Penalba A, Orset C, Azurmendi L, Llombart V, Simats A, Pecharroman E, Ventura O, Ribó M, Vivien D, Sanchez JC, Montaner J
Neurology 1526-632X
PMID : 33674361
KEYWORDS : Aged|Aged, 80 and over|Biomarkers|blood|Female|Hemorrhagic Stroke|blood|Humans|Ischemic Stroke|blood|Male|Sensitivity and Specificity
Show abstract [+]
To validate a panel of blood biomarkers to differentiate between ischemic stroke (IS) and intracerebral hemorrhage (ICH) in patients with suspected stroke.
Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses.
Hélie P, Camacho-Toledano C, Lesec L, Seillier C, Miralles AJ, Ortega MC, Guérit S, Lebas H, Bardou I, Vila-Del Sol V, Vivien D, Le Mauff B, Clemente D, Docagne F, Toutirais O
J Neuroinflammation 1742-2094
PMID : 33610187
KEYWORDS : Animals|Encephalomyelitis, Autoimmune, Experimental|blood|Female|Humans|Lymphocyte Activation|drug effects|Male|Mice|Mice, 129 Strain|Mice, Inbred C57BL|Mice, Knockout|Mice, Transgenic|Myeloid Cells|drug effects|Tissue Plasminogen Activator|deficiency
Show abstract [+]
Tissue plasminogen activator (tPA) is a serine protease involved in fibrinolysis. It is released by endothelial cells, but also expressed by neurons and glial cells in the central nervous system (CNS). Interestingly, this enzyme also contributes to pathological processes in the CNS such as neuroinflammation by activating microglia and increasing blood-brain barrier permeability. Nevertheless, its role in the control of adaptive and innate immune response remains poorly understood.
New Opportunities for Diagnosis and Prognosis of Stroke: The Benefits of Across Border Approaches.
Vivien D
Hamostaseologie 2567-5761
PMID : 33588450
KEYWORDS : Humans|Prognosis|Stroke|diagnosis
Show abstract [+]
Ischemic stroke is a leading cause of disability, with its treatment not yet optimal. It is thus mandatory to make preclinical research on this topic more efficient. This review summarizes current development of research aimed to improve diagnosis and prognosis of ischemic stroke. For more details, see our recent review published in Lancet Neurology.
New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases.
Boltze J, Aronowski JA, Badaut J, Buckwalter MS, Caleo M, Chopp M, Dave KR, Didwischus N, Dijkhuizen RM, Doeppner TR, Dreier JP, Fouad K, Gelderblom M, Gertz K, Golubczyk D, Gregson BA, Hamel E, Hanley DF, Härtig W, Hummel FC, Ikhsan M, Janowski M, Jolkkonen J, Karuppagounder SS, Keep RF, Koerte IK, Kokaia Z, Li P, Liu F, Lizasoain I, Ludewig P, Metz GAS, Montagne A, Obenaus A, Palumbo A, Pearl M, Perez-Pinzon M, Planas AM, Plesnila N, Raval AP, Rueger MA, Sansing LH, Sohrabji F, Stagg CJ, Stetler RA, Stowe AM, Sun D, Taguchi A, Tanter M, Vay SU, Vemuganti R, Vivien D, Walczak P, Wang J, Xiong Y, Zille M
Front Aging Neurosci 1663-4365
PMID : 33584250
Show abstract [+]
The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.
Association of quality of life with structural, functional and molecular brain imaging in community-dwelling older adults.
Ourry V, Gonneaud J, Landeau B, Moulinet I, Touron E, Dautricourt S, Le Du G, Mézenge F, André C, Bejanin A, Sherif S, Marchant NL, Paly L, Poisnel G, Vivien D, Chocat A, Quillard A, Ferrand Devouge E, de la Sayette V, Rauchs G, Arenaza-Urquijo EM, Chételat G,
Neuroimage 1095-9572
PMID : 33549750
KEYWORDS : Aged|Aged, 80 and over|Aging|physiology|Brain|diagnostic imaging|Diffusion Magnetic Resonance Imaging|methods|Female|Humans|Independent Living|psychology|Male|Molecular Imaging|methods|Quality of Life|psychology
Show abstract [+]
As the population ages, maintaining mental health and well-being of older adults is a public health priority. Beyond objective measures of health, self-perceived quality of life (QoL) is a good indicator of successful aging. In older adults, it has been shown that QoL is related to structural brain changes. However, QoL is a multi-faceted concept and little is known about the specific relationship of each QoL domain to brain structure, nor about the links with other aspects of brain integrity, including white matter microstructure, brain perfusion and amyloid deposition, which are particularly relevant in aging. Therefore, we aimed to better characterize the brain biomarkers associated with each QoL domain using a comprehensive multimodal neuroimaging approach in older adults.
Rate of Rebleed and Retreatment of Previously Treated Intracranial Aneurysms.
Metayer T, Terrier L, de Schlichting E, Lechanoine F, Bougaci N, Derrey S, Barbier C, Papagiannaki C, Ashraf A, Tahon F, Leplus A, Naveau M, Gay E, Emery E, Lonjon M, Vivien D, Gaberel T
World Neurosurg 1878-8769
PMID : 33497825
KEYWORDS : Adult|Aged|Aneurysm, Ruptured|therapy|Cohort Studies|Endovascular Procedures|methods|Female|Follow-Up Studies|Humans|Intracranial Aneurysm|therapy|Kaplan-Meier Estimate|Male|Microsurgery|methods|Middle Aged|Postoperative Complications|epidemiology|Recurrence|Reoperation|statistics & numerical data|Retreatment|statistics & numerical data|Survival Analysis
Show abstract [+]
Intracranial aneurysms (IAs) can be treated through endovascular treatment (EVT) or microsurgery (MS). Treated IAs can recanalize, which can lead to rupture or retreatment.
Single- and two- chain tissue type plasminogen activator treatments differentially influence cerebral recovery after stroke.
Anfray A, Brodin C, Drieu A, Potzeha F, Dalarun B, Agin V, Vivien D, Orset C
Exp Neurol 1090-2430
PMID : 33453214
KEYWORDS : Animals|Fibrinolytic Agents|pharmacology|Male|Mice|Recombinant Proteins|pharmacology|Recovery of Function|drug effects|Stroke|Tissue Plasminogen Activator|pharmacology
Show abstract [+]
Tissue type Plasminogen Activator (tPA), named alteplase (Actilyse®) under its commercial form, is currently the only pharmacological treatment approved during the acute phase of ischemic stroke, used either alone or combined with thrombectomy. Interestingly, the commercial recombinant tPA (rtPA) contains two physiological forms of rtPA: the single chain rtPA (sc-rtPA) and the two-chains rtPA (tc-rtPA), with differential properties demonstrated in vitro. Using a relevant mouse model of thromboembolic stroke, we have investigated the overall effects of these two forms of rtPA when infused early after stroke onset (i.e. 20 min) on recanalization, lesion volumes, alterations of the integrity of the blood brain barrier and functional recovery. Our data reveal that there is no difference in the capacity of sc-rtPA and tc-rtPA to promote fibrinolysis and reperfusion of the tissue. However, compared to sc-rtPA, tc-rtPA is less efficient to reduce lesion volumes and to improve functional recovery, and is associated with an increased opening of the blood brain barrier. These data indicate better understanding of differential effects of these tPA forms might be important to ultimately improve stroke treatment.
Filling the gaps on stroke research: Focus on inflammation and immunity.
Levard D, Buendia I, Lanquetin A, Glavan M, Vivien D, Rubio M
Brain Behav Immun 1090-2139
PMID : 33017613
KEYWORDS : Animals|Brain Ischemia|drug therapy|Comorbidity|Disease Models, Animal|Humans|Immunity|immunology|Inflammation|immunology|Neuroprotection|immunology|Outcome Assessment, Health Care|Reperfusion|methods|Stroke|immunology|Stroke Rehabilitation|methods
Show abstract [+]
For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19. We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.
A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs.
Debatisse J, Wateau O, Cho TH, Costes N, Mérida I, Léon C, Langlois JB, Taborik F, Verset M, Portier K, Aggour M, Troalen T, Villien M, Makris N, Tourvieille C, Bars DL, Lancelot S, Confais J, Oudotte A, Nighoghossian N, Ovize M, Vivien D, Contamin H, Agin V, Canet-Soulas E, Eker OF
J Cereb Blood Flow Metab 1559-7016
PMID : 32428423
KEYWORDS : Animals|Behavior, Animal|Blood-Brain Barrier|Disease Models, Animal|Endovascular Procedures|methods|Executive Function|Infarction, Middle Cerebral Artery|diagnostic imaging|Ischemic Stroke|diagnostic imaging|Macaca fascicularis|Magnetic Resonance Imaging|Male|Motor Skills|Positron-Emission Tomography|Reperfusion Injury|Thrombectomy|methods|Tomography, X-Ray Computed|Treatment Outcome
Show abstract [+]
Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.
2020
EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis.
Allas L, Brochard S, Rochoux Q, Ribet J, Dujarrier C, Veyssiere A, Aury-Landas J, Grard O, Leclercq S, Vivien D, Ea HK, Maubert E, Cohen-Solal M, Boumediene K, Agin V, Baugé C
Sci Rep 2045-2322
PMID : 33177650
KEYWORDS : Aged|Aged, 80 and over|Animals|Benzamides|pharmacology|Biphenyl Compounds|pharmacology|Cartilage, Articular|drug effects|Chondrocytes|drug effects|Disease Models, Animal|Enhancer of Zeste Homolog 2 Protein|antagonists & inhibitors|Gene Expression Regulation|Humans|Interleukin-1beta|pharmacology|Male|Mice, Inbred C57BL|Middle Aged|Morpholines|pharmacology|Nerve Growth Factor|metabolism|Organ Culture Techniques|Osteoarthritis|pathology|Pyridones|pharmacology
Show abstract [+]
Histone methyltransferase EZH2 is upregulated during osteoarthritis (OA), which is the most widespread rheumatic disease worldwide, and a leading cause of disability. This study aimed to assess the impact of EZH2 inhibition on cartilage degradation, inflammation and functional disability. In vitro, gain and loss of EZH2 function were performed in human articular OA chondrocytes stimulated with IL-1β. In vivo, the effects of EZH2 inhibition were investigated on medial meniscectomy (MMX) OA mouse model. The tissue alterations were assayed by histology and the functional disabilities of the mice by actimetry and running wheel. In vitro, EZH2 overexpression exacerbated the action of IL-1β in chondrocytes increasing the expression of genes involved in inflammation, pain (NO, PGE2, IL6, NGF) and catabolism (MMPs), whereas EZH2 inhibition by a pharmacological inhibitor, EPZ-6438, reduced IL-1β effects. Ex vivo, EZH2 inhibition decreased IL-1β-induced degradation of cartilage. In vivo, intra-articular injections of the EZH2 inhibitor reduced cartilage degradation and improved motor functions of OA mice. This study demonstrates that the pharmacological inhibition of the histone methyl-transferase EZH2 slows the progression of osteoarthritis and improves motor functions in an experimental OA model, suggesting that EZH2 could be an effective target for the treatment of OA by reducing catabolism, inflammation and pain.
Environmental enrichment alleviates the deleterious effects of stress in experimental autoimmune encephalomyelitis.
Fournier AP, Baudron E, Wagnon I, Aubert P, Vivien D, Neunlist M, Bardou I, Docagne F
Mult Scler J Exp Transl Clin 2055-2173
PMID : 33101703
Show abstract [+]
Clinical observations support the hypothesis that stressful events increase relapse occurrence in multiple sclerosis patients, while stress-reduction strategies can modulate this effect. However, a direct cause-effect relationship between stress level and relapse cannot be firmly established from these data.
White matter hyperintensities across the adult lifespan: relation to age, Aβ load, and cognition.
Garnier-Crussard A, Bougacha S, Wirth M, André C, Delarue M, Landeau B, Mézenge F, Kuhn E, Gonneaud J, Chocat A, Quillard A, Ferrand-Devouge E, de La Sayette V, Vivien D, Krolak-Salmon P, Chételat G
Alzheimers Res Ther 1758-9193
PMID : 33032654
KEYWORDS : Aged|Brain|diagnostic imaging|Cognition|Humans|Longevity|Magnetic Resonance Imaging|Middle Aged|Neuropsychological Tests|White Matter|diagnostic imaging
Show abstract [+]
White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical β-amyloid (Aβ) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults.
Ultrasensitive molecular imaging of intestinal mucosal inflammation using leukocyte-mimicking particles targeted to MAdCAM-1 in mice.
Fournier AP, Martinez de Lizarrondo S, Rateau A, Gerard-Brisou A, Waldner MJ, Neurath MF, Vivien D, Docagne F, Gauberti M
Sci Transl Med 1946-6242
PMID : 32908005
KEYWORDS : Animals|Humans|Immunoglobulins|Inflammation|Intestinal Mucosa|Leukocytes|Mice|Molecular Imaging|Mucoproteins
Show abstract [+]
Mucosal tissues play critical roles in health and disease as the primary barrier between the external world and the inner body, lining the digestive, respiratory, urinary, mammary, and reproductive tracts. Clinical evaluation of mucosal tissues is currently performed using endoscopy, such as ileocolonoscopy for the intestinal mucosa, which causes substantial patient discomfort and can lead to organ damage. Here, we developed a contrast agent for molecular magnetic resonance imaging (MRI) that is targeted to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), an adhesion molecule overexpressed by inflamed mucosal tissues. We investigated the diagnostic performance of molecular MRI of MAdCAM-1 to detect mucosal inflammation in several models of acute and chronic intestinal inflammation in mice. We demonstrated that molecular MRI of MAdCAM-1 reveals disease activity and can evaluate the response to inflammatory treatments along the whole intestinal mucosa in clinically relevant models of inflammatory bowel diseases. We also provide evidence that this technique can detect low, subclinical mucosal inflammation. Molecular MRI of MAdCAM-1 has potential applications in early diagnosis, longitudinal follow-up, and therapeutic response monitoring in diseases affecting mucosal tissues, such as inflammatory bowel diseases.
Autoimmune encephalitis mediated by B-cell response against N-methyl-d-aspartate receptor.
Wagnon I, Hélie P, Bardou I, Regnauld C, Lesec L, Leprince J, Naveau M, Delaunay B, Toutirais O, Lemauff B, Etard O, Vivien D, Agin V, Macrez R, Maubert E, Docagne F
Brain 1460-2156
PMID : 32893288
KEYWORDS : Animals|Autoantibodies|blood|B-Lymphocytes|immunology|Encephalitis|blood|Hashimoto Disease|blood|Male|Mice|Mice, Inbred C57BL|Nerve Tissue Proteins|immunology|Receptors, N-Methyl-D-Aspartate|immunology
Show abstract [+]
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease characterized by an antibody-mediated autoimmune response against NMDAR. Recent studies have shown that anti-NMDAR antibodies are involved in the pathophysiology of the disease. However, the upstream immune and inflammatory processes responsible for this pathogenic response are still poorly understood. Here, we immunized mice against the region of NMDA receptor containing the N368/G369 amino acids, previously implicated in a pathogenic response. This paradigm induced encephalopathy characterized by blood-brain barrier opening, periventricular T2-MRI hyperintensities and IgG deposits into the brain parenchyma. Two weeks after immunization, mice developed clinical symptoms reminiscent of encephalitis: anxiety- and depressive-like behaviours, spatial memory impairment (without motor disorders) and increased sensitivity to seizures. This response occurred independently of overt T-cell recruitment. However, it was associated with B220+ (B cell) infiltration towards the ventricles, where they differentiated into CD138+ cells (plasmocytes). Interestingly, these B cells originated from peripheral lymphoid organs (spleen and cervical lymphoid nodes). Finally, blocking the B-cell response using a depleting cocktail of antibodies reduced the severity of symptoms in encephalitis mice. This study demonstrates that the B-cell response can lead to an autoimmune reaction against NMDAR that drives encephalitis-like behavioural impairments. It also provides a relevant platform for dissecting encephalitogenic mechanisms in an animal model, and enables the testing of therapeutic strategies targeting the immune system in anti-NMDAR encephalitis.
An overview of the perspectives on experimental models and new therapeutic targets in giant cell arteritis.
Deshayes S, de Boysson H, Dumont A, Vivien D, Manrique A, Aouba A
Autoimmun Rev 1873-0183
PMID : 32810608
KEYWORDS : Aortic Aneurysm|Aortitis|Giant Cell Arteritis|Humans|Models, Theoretical|Temporal Arteries
Show abstract [+]
Giant cell arteritis (GCA) is the most frequent systemic vasculitis occurring in adults older than 50 years, and aortitis is described in 40% to 80% of patients. The treatment relies on corticosteroids, but it is complicated by high rates of relapses and adverse effects and may be unable to completely inhibit aortic inflammation. Moreover, most of the current data regarding the pathophysiology of GCA have been obtained from bioassays using blood and temporal arteries, as well as histological analyses of temporal arteries and very few aortic aneurysms from patients with GCA. The limitations of these analyses prevent researchers from determining the implications of specific targets and studying the effects of targeted treatments. Several experimental models have been developed, but to date, a perfect model is not available for GCA, particularly for studies of large-vessel vasculitis. The review focuses on the perspectives on experimental models and new therapeutic targets in giant cell arteritis.
Validation of a stroke model in rat compatible with rt-PA-induced thrombolysis: new hope for successful translation to the clinic.
Arkelius K, Vivien D, Orset C, Ansar S
Sci Rep 2045-2322
PMID : 32699371
KEYWORDS : Animals|Brain|diagnostic imaging|Disease Models, Animal|Fibrinolytic Agents|therapeutic use|Magnetic Resonance Imaging|Male|Middle Cerebral Artery|Rats|Rats, Wistar|Stroke|diagnostic imaging|Thromboembolism|drug therapy|Tissue Plasminogen Activator|therapeutic use
Show abstract [+]
The recent clinical trial (DAWN) suggests that recanalization treatment may be beneficial up to 24 h after stroke onset, thus re-opening avenues for development of new therapeutic strategies. Unfortunately, there is a continuous failure of drugs in clinical trials and one of the major reasons proposed for this translational roadblock is the animal models. Therefore, the purpose of this study was to validate a new thromboembolic stroke rat model that mimics the human pathology, and that can be used for evaluating new strategies to save the brain in conditions compatible with recanalization. Stroke was induced by injection of thrombin into the middle cerebral artery. Recombinant tissue-type plasminogen activator (rt-PA) or saline was administrated at 1 h/4 h after stroke onset, and outcome was evaluated after 24 h. Induced ischemia resulted in reproducible cortical brain injuries causing a decrease in neurological function 24 h after stroke onset. Early rt-PA treatment resulted in recanalization, reduced infarct size and improved neurological functions, while late rt-PA treatment showed no beneficial effects and caused hemorrhagic transformation in 25% of the rats. This validated and established model's resemblance to human ischemic stroke and high translational potential, makes it an important tool in the development of new therapeutic strategies for stroke.
Early Ultrafast Ultrasound Imaging of Cerebral Perfusion correlates with Ischemic Stroke outcomes and responses to treatment in Mice.
Hingot V, Brodin C, Lebrun F, Heiles B, Chagnot A, Yetim M, Gauberti M, Orset C, Tanter M, Couture O, Deffieux T, Vivien D
Theranostics 1838-7640
PMID : 32685000
KEYWORDS : Animals|Brain|blood supply|Cerebrovascular Circulation|Disease Models, Animal|Fibrinolytic Agents|administration & dosage|Humans|Intravital Microscopy|instrumentation|Magnetic Resonance Imaging|Male|Mice|Middle Cerebral Artery|diagnostic imaging|Proof of Concept Study|Recombinant Proteins|administration & dosage|Thrombolytic Therapy|Thrombotic Stroke|chemically induced|Time Factors|Tissue Plasminogen Activator|administration & dosage|Ultrasonography, Doppler|instrumentation
Show abstract [+]
In the field of ischemic cerebral injury, precise characterization of neurovascular hemodynamic is required to select candidates for reperfusion treatments. It is thus admitted that advanced imaging-based approaches would be able to better diagnose and prognose those patients and would contribute to better clinical care. Current imaging modalities like MRI allow a precise diagnostic of cerebral injury but suffer from limited availability and transportability. The recently developed ultrafast ultrasound could be a powerful tool to perform emergency imaging and long term follow-up of cerebral perfusion, which could, in combination with MRI, improve imaging solutions for neuroradiologists. In this study, in a model of in situ thromboembolic stroke in mice, we compared a control group of non-treated mice (N=10) with a group receiving the gold standard pharmacological stroke therapy (N=9). We combined the established tool of magnetic resonance imaging (7T MRI) with two innovative ultrafast ultrasound methods, ultrafast Doppler and Ultrasound Localization Microscopy, to image the cerebral blood volumes at early and late times after stroke onset and compare with the formation of ischemic lesions Our study shows that ultrafast ultrasound can be used through the mouse skull to monitor cerebral perfusion during ischemic stroke. In our data, the monitoring of the reperfusion following thrombolytic within the first 2 h post stroke onset matches ischemic lesions measured 24 h. Moreover, similar results can be made with Ultrasound Localization Microscopy which could make it applicable to human patients in the future. We thus provide the proof of concept that in a mouse model of thromboembolic stroke with an intact skull, early ultrafast ultrasound can be indicative of responses to treatment and cerebral tissue fates following stroke. It brings new tools to study ischemic stroke in preclinical models and is the first step prior translation to the clinical settings.
Fast Stent Retrieval Improves Recanalization Rates of Thrombectomy: Experimental Study on Different Thrombi.
Soize S, Pierot L, Mirza M, Gunning G, Gilvarry M, Gawlitza M, Vivien D, Zuber M, Touzé E
AJNR Am J Neuroradiol 1936-959X
PMID : 32409312
KEYWORDS : Aged|Brain Ischemia|etiology|Female|Humans|Male|Models, Anatomic|Stroke|etiology|Thrombectomy|instrumentation|Thrombosis|complications|Time Factors
Show abstract [+]
About 20% of patients with acute ischemic stroke due to large-artery occlusion do not achieve recanalization with mechanical thrombectomy. We aimed to determine whether the speed of retrieval of the stent retriever influences the efficacy in removing different clot types.
Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial.
André C, Rehel S, Kuhn E, Landeau B, Moulinet I, Touron E, Ourry V, Le Du G, Mézenge F, Tomadesso C, de Flores R, Bejanin A, Sherif S, Delcroix N, Manrique A, Abbas A, Marchant NL, Lutz A, Klimecki OM, Collette F, Arenaza-Urquijo EM, Poisnel G, Vivien D, Bertran F, de la Sayette V, Chételat G, Rauchs G,
JAMA Neurol 2168-6157
PMID : 32202593
KEYWORDS : Aged|Alzheimer Disease|Amyloidogenic Proteins|metabolism|Biomarkers|analysis|Brain|metabolism|Cross-Sectional Studies|Female|Gray Matter|pathology|Humans|Independent Living|Male|Middle Aged|Positron-Emission Tomography|Sleep Apnea Syndromes|complications
Show abstract [+]
Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear.
Cranioplasty Reverses Dysfunction of the Solutes Distribution in the Brain Parenchyma After Decompressive Craniectomy.
Borha A, Chagnot A, Goulay R, Emery E, Vivien D, Gaberel T
Neurosurgery 1524-4040
PMID : 32097469
KEYWORDS : Animals|Brain|metabolism|Brain Injuries, Traumatic|surgery|Cerebrospinal Fluid|metabolism|Decompressive Craniectomy|adverse effects|Extracellular Fluid|metabolism|Glymphatic System|metabolism|Male|Mice|Plastic Surgery Procedures|Skull|surgery
Show abstract [+]
Solutes distribution by the intracranial cerebrospinal fluid (CSF) fluxes along perivascular spaces and through interstitial fluid (ISF) play a key role in the clearance of brain metabolites, with essential functions in maintaining brain homeostasis.
Alcohol exposure-induced neurovascular inflammatory priming impacts ischemic stroke and is linked with brain perivascular macrophages.
Drieu A, Lanquetin A, Levard D, Glavan M, Campos F, Quenault A, Lemarchand E, Naveau M, Pitel AL, Castillo J, Vivien D, Rubio M
JCI Insight 2379-3708
PMID : 31990687
KEYWORDS : Alcohol Drinking|Animals|Biomarkers|metabolism|Blood Vessels|cytology|Brain Ischemia|chemically induced|Ethanol|toxicity|Female|Humans|Inflammation|metabolism|Ischemic Stroke|chemically induced|Macrophages|drug effects|Male|Mice|Vasculitis|chemically induced
Show abstract [+]
Alcohol abuse is a major public health problem worldwide, causing a wide range of preventable morbidity and mortality. In this translational study, we show that heavy drinking (HD) (≥6 standard drinks/day) is independently associated with a worse outcome for ischemic stroke patients. To study the underlying mechanisms of this deleterious effect of HD, we performed an extensive analysis of the brain inflammatory responses of mice chronically exposed or not to 10% alcohol before and after ischemic stroke. Inflammatory responses were analyzed at the parenchymal, perivascular, and vascular levels by using transcriptomic, immunohistochemical, in vivo 2-photon microscopy and molecular MRI analyses. Alcohol-exposed mice show, in the absence of any other insult, a neurovascular inflammatory priming (i.e., an abnormal inflammatory status including an increase in brain perivascular macrophages [PVM]) associated with exacerbated inflammatory responses after a secondary insult (ischemic stroke or LPS challenge). Similar to our clinical data, alcohol-exposed mice showed larger ischemic lesions. We show here that PVM are key players on this aggravating effect of alcohol, since their specific depletion blocks the alcohol-induced aggravation of ischemic lesions. This study opens potentially new therapeutic avenues aiming at blocking alcohol-induced exacerbation of the neurovascular inflammatory responses triggered after ischemic stroke.
Nonionotropic Action of Endothelial NMDA Receptors on Blood-Brain Barrier Permeability via Rho/ROCK-Mediated Phosphorylation of Myosin.
Mehra A, Guérit S, Macrez R, Gosselet F, Sevin E, Lebas H, Maubert E, De Vries HE, Bardou I, Vivien D, Docagne F
J Neurosci 1529-2401
PMID : 31953371
KEYWORDS : Animals|Blood-Brain Barrier|drug effects|Cell Line|Cerebral Cortex|drug effects|Endothelial Cells|drug effects|Excitatory Amino Acid Agonists|pharmacology|Male|Mice|Myosins|metabolism|N-Methylaspartate|pharmacology|Neurons|drug effects|Permeability|Phosphorylation|drug effects|Receptors, N-Methyl-D-Aspartate|agonists|Signal Transduction|drug effects|Tissue Plasminogen Activator|pharmacology|Tumor Necrosis Factor-alpha|pharmacology|rho GTP-Binding Proteins|metabolism|rho-Associated Kinases|metabolism
Show abstract [+]
Increase in blood-brain barrier (BBB) permeability is a crucial step in neuroinflammatory processes. We previously showed that N Methyl D Aspartate Receptor (NMDARs), expressed on cerebral endothelial cells forming the BBB, regulate immune cell infiltration across this barrier in the mouse. Here, we describe the mechanism responsible for the action of NMDARs on BBB permeabilization. We report that mouse CNS endothelial NMDARs display the regulatory GluN3A subunit. This composition confers to NMDARs' unconventional properties: these receptors do not induce Ca2+ influx but rather show nonionotropic properties. In inflammatory conditions, costimulation of human brain endothelial cells by NMDA agonists (NMDA or glycine) and the serine protease tissue plasminogen activator, previously shown to potentiate NMDAR activity, induces metabotropic signaling via the Rho/ROCK pathway. This pathway leads to an increase in permeability via phosphorylation of myosin light chain and subsequent shrinkage of human brain endothelial cells. Together, these data draw a link between NMDARs and the cytoskeleton in brain endothelial cells that regulates BBB permeability in inflammatory conditions. The authors describe how NMDARs expressed on endothelial cells regulate blood-brain barrier function via myosin light chain phosphorylation and increase in permeability. They report that these non-neuronal NMDARs display distinct structural, functional, and pharmacological features than their neuronal counterparts.
Neonatal cerebral hypoxia-ischemia in mice triggers age-dependent vascular effects and disabilities in adults; implication of tissue plasminogen activator (tPA).
Dupré N, Arabo A, Orset C, Maucotel J, Detroussel Y, Hauchecorne M, Gonzalez BJ, Marret S, Vivien D, Leroux P
Exp Neurol 1090-2430
PMID : 31697944
KEYWORDS : Animals|Animals, Newborn|Behavior, Animal|physiology|Blood-Brain Barrier|physiopathology|Capillary Permeability|physiology|Hypoxia-Ischemia, Brain|metabolism|Magnetic Resonance Imaging|Matrix Metalloproteinase 9|metabolism|Mice|Mice, Inbred C57BL|Mice, Knockout|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Neonatal encephalopathy frequently results from hypoxia-ischemia (HI) or inflammation in preterm or term neonates. Neuropathology depends on cerebral development at insult time, but the poor correlation of neuromotor, cognitive, and behavioral disabilities in infancy with initial imaging and clinical records precludes early prognosis. The Rice-Vannucci HI procedure was applied to wild type and tissue plasminogen activator knockout (tPA-KO) mice as surrogates for human preterm (with five-day-old postnatal (P5) mice) or human term (with ten-day-old postnatal (P10) mice). Acute and delayed T2-magnetic resonance imaging (T2-MRI) signals and cognitive deficits in adulthood (spatial memory and social interaction) were investigated in the same animals. Early vascular tPA and matrix metalloproteinase-9 (MMP-9) activities, blood-brain barrier permeability to water or IgG, and microglial activation were assessed separately. HI in P5 or P10 mice induced early hemisphere swelling in T2-MRI scans, and a delayed atrophy of the cortex and hippocampus, but affected white matter in the P5 group only, irrespective of the wild type or tPA-KO genotype. Adults had no motor disabilities, but we did find HI-induced age-dependent deficits, preferentially social interaction and activity in P5 mice, and spatial learning in P10 mice. In P5 mice, tPA-KO prevented MMP-9 activation, IgG extravasation, microglial activation, and behavior impairments. In P10 mice, MMP-9 activation and inflammatory processes remained in the hippocampus of the tPA-KO group, and also contributed to persistent spatial learning deficits. Perinatal HI in mice mimicked the unpredictability of outcomes from imaging in human clinics. Delayed deficits appeared associated to vascular dysfunction-induced inflammation, which recalls our previous work showing major vascular maturation between P5 and P10 stages. Using omics to explore neural, glial, or brain vessel markers in neonate blood may be a promising perspective to identify pertinent prognostic tools.
Circulating tPA contributes to neurovascular coupling by a mechanism involving the endothelial NMDA receptors.
Anfray A, Drieu A, Hingot V, Hommet Y, Yetim M, Rubio M, Deffieux T, Tanter M, Orset C, Vivien D
J Cereb Blood Flow Metab 1559-7016
PMID : 31665952
KEYWORDS : Animals|Brain|diagnostic imaging|Cerebral Arteries|physiology|Cerebrovascular Circulation|physiology|Endothelium, Vascular|physiology|Immunohistochemistry|Male|Mice|Mice, Inbred C57BL|Mice, Knockout|Neuroimaging|Neurovascular Coupling|physiology|Receptors, N-Methyl-D-Aspartate|physiology|Rheology|Tissue Plasminogen Activator|blood|Transfection|Ultrasonography
Show abstract [+]
The increase of cerebral blood flow evoked by neuronal activity is essential to ensure enough energy supply to the brain. In the neurovascular unit, endothelial cells are ideally placed to regulate key neurovascular functions of the brain. Nevertheless, some outstanding questions remain about their exact role neurovascular coupling (NVC). Here, we postulated that the tissue-type plasminogen activator (tPA) present in the circulation might contribute to NVC by a mechanism dependent of its interaction with endothelial N-Methyl-D-Aspartate Receptor (NMDAR). To address this question, we used pharmacological and genetic approaches to interfere with vascular tPA-dependent NMDAR signaling, combined with laser speckle flowmetry, intravital microscopy and ultrafast functional ultrasound in vivo imaging. We found that the tPA present in the blood circulation is capable of potentiating the cerebral blood flow increase induced by the activation of the mouse somatosensorial cortex, and that this effect is mediated by a tPA-dependent activation of NMDAR expressed at the luminal part of endothelial cells of arteries. Although blood molecules, such as acetylcholine, bradykinin or ATP are known to regulate vascular tone and induce vessel dilation, our present data provide the first evidence that circulating tPA is capable of influencing neurovascular coupling (NVC).
Immune Responses and Anti-inflammatory Strategies in a Clinically Relevant Model of Thromboembolic Ischemic Stroke with Reperfusion.
Drieu A, Buendia I, Levard D, Hélie P, Brodin C, Vivien D, Rubio M
Transl Stroke Res 1868-601X
PMID : 31522409
KEYWORDS : Animals|Anti-Inflammatory Agents|administration & dosage|Brain|drug effects|Brain Ischemia|etiology|Disease Models, Animal|Ischemic Stroke|etiology|Male|Mice|Minocycline|administration & dosage|Natalizumab|administration & dosage|Reperfusion Injury|etiology|Thromboembolism|complications
Show abstract [+]
The poor clinical relevance of experimental models of stroke contributes to the translational failure between preclinical and clinical studies testing anti-inflammatory molecules for ischemic stroke. Here, we (i) describe the time course of inflammatory responses triggered by a thromboembolic model of ischemic stroke and (ii) we examine the efficacy of two clinically tested anti-inflammatory drugs: Minocycline or anti-CD49d antibodies (tested in stroke patients as Natalizumab) administered early (1 h) or late (48 h) after stroke onset. Radiological (lesion volume) and neurological (grip test) outcomes were evaluated at 24 h and 5 days after stroke. Immune cell responses peaked 48 h after stroke onset. Myeloid cells (microglia/macrophages, dendritic cells, and neutrophils) were already increased 24 h after stroke onset, peaked at 48 h, and remained increased-although to a lesser extent-5 days after stroke onset. CD8+ and CD4+ T-lymphocytes infiltrated the ipsilateral hemisphere later on (only from 48 h). These responses occurred together with a progressive blood-brain barrier leakage at the lesion site, starting 24 h after stroke onset. Lesion volume was maximal 24-48 h after stroke onset. Minocycline reduced both lesion volume and neurological deficit only when administered early after stroke onset. The blockade of leukocyte infiltration by anti-CD49d had no impact on lesion volume or long-term neurological deficit, independently of the timing of treatment. Our data are in accordance with the results of previous clinical reports on the use of Minocycline and Natalizumab on ischemic stroke. We thus propose the use of this clinically relevant model of thromboembolic stroke with recanalization for future testing of anti-inflammatory strategies for stroke.
Glutamate controls vessel-associated migration of GABA interneurons from the pial migratory route via NMDA receptors and endothelial protease activation.
Léger C, Dupré N, Aligny C, Bénard M, Lebon A, Henry V, Hauchecorne M, Galas L, Frebourg T, Leroux P, Vivien D, Lecointre M, Marret S, Gonzalez BJ
Cell Mol Life Sci 1420-9071
PMID : 31392351
KEYWORDS : Animals|Animals, Newborn|Blood Vessels|metabolism|Brain Mapping|Cell Movement|genetics|Endothelial Cells|metabolism|GABAergic Neurons|metabolism|Gene Expression Regulation|genetics|Glutamate Decarboxylase|genetics|Glutamic Acid|genetics|Humans|Interneurons|metabolism|Matrix Metalloproteinase 9|genetics|Mice|Mice, Transgenic|Neurogenesis|genetics|Receptors, N-Methyl-D-Aspartate|genetics|Somatosensory Cortex|blood supply|Tissue Plasminogen Activator|genetics|gamma-Aminobutyric Acid|genetics
Show abstract [+]
During cortex development, fine interactions between pyramidal cells and migrating GABA neurons are required to orchestrate correct positioning of interneurons, but cellular and molecular mechanisms are not yet clearly understood. Functional and age-specific expression of NMDA receptors by neonate endothelial cells suggests a vascular contribution to the trophic role of glutamate during cortical development. Associating functional and loss-of-function approaches, we found that glutamate stimulates activity of the endothelial proteases MMP-9 and t-PA along the pial migratory route (PMR) and radial cortical microvessels. Activation of MMP-9 was NMDAR-dependent and abrogated in t-PA-/- mice. Time-lapse recordings revealed that glutamate stimulated migration of GABA interneurons along vessels through an NMDAR-dependent mechanism. In Gad67-GFP mice, t-PA invalidation and in vivo administration of an MMP inhibitor impaired positioning of GABA interneurons in superficial cortical layers, whereas Grin1 endothelial invalidation resulted in a strong reduction of the thickness of the pial migratory route, a marked decrease of the glutamate-induced MMP-9-like activity along the PMR and a depopulation of interneurons in superficial cortical layers. This study supports that glutamate controls the vessel-associated migration of GABA interneurons by regulating the activity of endothelial proteases. This effect requires endothelial NMDAR and is t-PA-dependent. These neurodevelopmental data reinforce the debate regarding safety of molecules with NMDA-antagonist properties administered to preterm and term neonates.
2019
Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments.
Party H, Dujarrier C, Hébert M, Lenoir S, Martinez de Lizarrondo S, Delépée R, Fauchon C, Bouton MC, Obiang P, Godefroy O, Save E, Lecardeur L, Chabry J, Vivien D, Agin V
Acta Neuropathol Commun 2051-5960
PMID : 31610810
KEYWORDS : Animals|Brain|metabolism|Brain-Derived Neurotrophic Factor|metabolism|Depression|metabolism|Depressive Disorder, Major|metabolism|Disease Models, Animal|Dopamine|metabolism|Male|Mice, Inbred C57BL|Mice, Knockout|Plasminogen Activator Inhibitor 1|genetics|Serotonin|metabolism|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, thus ranking among the major causes of disability and morbidity worldwide. To date, genetic and environmental determinants of MDD remain mostly unknown. Here, we investigated whether and how the Plasminogen Activator Inhibitor-1 (PAI-1) may contribute to MDD. We first examined the phenotype of PAI-1 knockout (PAI-1-/-) and wild-type (PAI-1+/+) male mice with a range of behavioral tests assessing depressive-like behaviors (n = 276). We next investigated the mechanisms relating PAI-1 to MDD using molecular, biochemical and pharmacological analyzes. We demonstrate here that PAI-1 plays a key role in depression by a mechanism independent of the tissue-type Plasminogen Activator (tPA) - Brain-Derived Neurotrophic Factor (BDNF) axis, but associated with impaired metabolisms of serotonin and dopamine. Our data also reveal that PAI-1 interferes with therapeutic responses to selective serotonin reuptake inhibitors (escitalopram, fluoxetine). We thus highlight a new genetic preclinical model of depression, with the lack of PAI-1 as a factor of predisposition to MDD. Altogether, these original data reveal that PAI-1 should be now considered as a key player of MDD and as a potential target for the development of new drugs to cure depressive patients resistant to current treatments.
Longitudinal Molecular Magnetic Resonance Imaging of Endothelial Activation after Severe Traumatic Brain Injury.
Vegliante G, Tolomeo D, Drieu A, Rubio M, Micotti E, Moro F, Vivien D, Forloni G, Ali C, Zanier ER
J Clin Med 2077-0383
PMID : 31366109
Show abstract [+]
Traumatic brain injury (TBI) is a major cause of death and disability. Despite progress in neurosurgery and critical care, patients still lack a form of neuroprotective treatment that can counteract or attenuate injury progression. Inflammation after TBI is a key modulator of injury progression and neurodegeneration, but its spatiotemporal dissemination is only partially known. In vivo approaches to study post-traumatic inflammation longitudinally are pivotal for monitoring injury progression/recovery and the effectiveness of therapeutic approaches. Here, we provide a minimally invasive, highly sensitive in vivo molecular magnetic resonance imaging (MRI) characterization of endothelial activation associated to neuroinflammatory response after severe TBI in mice, using microparticles of iron oxide targeting P-selectin (MPIOs-α-P-selectin). Strong endothelial activation was detected from 24 h in perilesional regions, including the cortex and hippocampus, and peaked in intensity and diffusion at two days, then partially decreased but persisted up to seven days and was back to baseline 15 days after injury. There was a close correspondence between MPIOs-α-P-selectin signal voids and the P-selectin stained area, confirming maximal endothelial activation at two days. Molecular MRI markers of inflammation may thus represent a useful tool to evaluate in vivo endothelial activation in TBI and monitoring the responses to therapeutic agents targeting vascular activation and permeability.
In vivo ultrasound-activated delivery of recombinant tissue plasminogen activator from the cavity of sub-micrometric capsules.
Correa-Paz C, Navarro Poupard MF, Polo E, Rodríguez-Pérez M, Taboada P, Iglesias-Rey R, Hervella P, Sobrino T, Vivien D, Castillo J, Del Pino P, Campos F, Pelaz B
J Control Release 1873-4995
PMID : 31310784
KEYWORDS : Administration, Intravenous|Animals|Brain Ischemia|drug therapy|Capsules|Drug Delivery Systems|Fibrinolytic Agents|administration & dosage|Male|Mice|Recombinant Proteins|Stroke|drug therapy|Tissue Plasminogen Activator|administration & dosage|Ultrasonic Waves
Show abstract [+]
External stimuli such as light, magnetic fields or ultrasounds allow for controlled drug release from nanocarriers with spatiotemporal resolution. Such tetherless approaches may become a straightforward solution to overcome the specificity problems typically associated with nanomedicines. Most of current nanomedicines suffer of very low specificity in vivo, thus rendering efficient targeted delivery among the most wanted breakthroughs in the fields of nanotechnology and medicine. Here we present a sonosensitive, sub-micrometric layer-by-layer capsule system for ultrasound-controlled delivery of macromolecules in vivo. As a proof of concept, the serine protease recombinant tissue plasminogen activator (rtPA), a thrombolytic drug widely employed for the treatment of acute ischemic stroke and other thromboembolic pathologies, is used as encapsulated active compound. The activity of encapsulated rtPA and its ultrasound-induced delivery from the cavity of the capsules are demonstrated. We show, first, that rtPA encapsulation prevents its endogenous biological inactivation and do not interfere with the thrombolytic activity of the drug. Second, upon ultrasound application, delivery of rtPA promotes breakdown of blood clots in vitro. Finally, the ultrasound-triggered in vivo delivery of rtPA from capsules intravenously administrated in mice is demonstrated.
Cross-sectional and longitudinal characterization of SCD patients recruited from the community versus from a memory clinic: subjective cognitive decline, psychoaffective factors, cognitive performances, and atrophy progression over time.
Kuhn E, Moulinet I, Perrotin A, La Joie R, Landeau B, Tomadesso C, Bejanin A, Sherif S, De La Sayette V, Desgranges B, Vivien D, Poisnel G, Chételat G
Alzheimers Res Ther 1758-9193
PMID : 31286994
KEYWORDS : Aged|Aged, 80 and over|Alzheimer Disease|diagnosis|Anxiety|diagnosis|Biomarkers|Cognitive Dysfunction|diagnosis|Cross-Sectional Studies|Depression|diagnosis|Diagnostic Self Evaluation|Disease Progression|Female|Follow-Up Studies|Gray Matter|diagnostic imaging|Humans|Longitudinal Studies|Magnetic Resonance Imaging|Male|Memory Disorders|diagnosis|Mental Status and Dementia Tests|Middle Aged|Neocortex|diagnostic imaging|Positron-Emission Tomography|Prodromal Symptoms
Show abstract [+]
Subjective cognitive decline (SCD) defines a heterogeneous population, part of which having Alzheimer's disease (AD). We aimed at characterizing SCD populations according to whether or not they referred to a memory clinic, by assessing the factors associated with increased AD risk.
Proteostasis During Cerebral Ischemia.
Thiebaut AM, Hedou E, Marciniak SJ, Vivien D, Roussel BD
Front Neurosci 1662-4548
PMID : 31275110
Show abstract [+]
Cerebral ischemia is a complex pathology involving a cascade of cellular mechanisms, which deregulate proteostasis and lead to neuronal death. Proteostasis refers to the equilibrium between protein synthesis, folding, transport, and protein degradation. Within the brain proteostasis plays key roles in learning and memory by controlling protein synthesis and degradation. Two important pathways are implicated in the regulation of proteostasis: the unfolded protein response (UPR) and macroautophagy (called hereafter autophagy). Both are necessary for cell survival, however, their over-activation in duration or intensity can lead to cell death. Moreover, UPR and autophagy can activate and potentiate each other to worsen the issue of cerebral ischemia. A better understanding of autophagy and ER stress will allow the development of therapeutic strategies for stroke, both at the acute phase and during recovery. This review summarizes the latest therapeutic advances implicating ER stress or autophagy in cerebral ischemia. We argue that the processes governing proteostasis should be considered together in stroke, rather than focusing either on ER stress or autophagy in isolation.
HLA-Class II Artificial Antigen Presenting Cells in CD4+ T Cell-Based Immunotherapy.
Couture A, Garnier A, Docagne F, Boyer O, Vivien D, Le-Mauff B, Latouche JB, Toutirais O
Front Immunol 1664-3224
PMID : 31156634
KEYWORDS : Antigen Presentation|Antigen-Presenting Cells|immunology|CD4-Positive T-Lymphocytes|immunology|Cancer Vaccines|immunology|Cell Proliferation|HLA Antigens|metabolism|Histocompatibility Antigens Class II|metabolism|Humans|Immunotherapy, Adoptive|methods|T-Lymphocytes, Regulatory|immunology
Show abstract [+]
CD4+ T cells differentiate into various T helper subsets characterized by distinct cytokine secreting profiles that confer them effector functions adapted to a variety of infectious or endogenous threats. Regulatory CD4+ T cells are another specialized subset that plays a fundamental role in the maintenance of immune tolerance to self-antigens. Manipulating effector or regulatory CD4+ T cells responses is a promising immunotherapy strategy for, respectively, chronical viral infections and cancer, or severe autoimmune diseases and transplantation. Adoptive cell therapy (ACT) is an emerging approach that necessitates defining robust and efficient methods for the in vitro expansion of antigen-specific T cells then infused into patients. To address this challenge, artificial antigen presenting cells (AAPCs) have been developed. They constitute a reliable and easily usable platform to stimulate and amplify antigen-specific CD4+ T cells. Here, we review the recent advances in understanding the functions of CD4+ T cells in immunity and in immune tolerance, and their use for ACT. We also describe the characteristics of different AAPC models and the way to improve their stimulating functions. Finally, we discuss the potential interest of these AAPCs, both as fundamental tools to decipher CD4+ T cell responses and as reagents to generate clinical grade antigen-specific CD4+ T cells for immunotherapy.
Post-synaptic Release of the Neuronal Tissue-Type Plasminogen Activator (tPA).
Lenoir S, Varangot A, Lebouvier L, Galli T, Hommet Y, Vivien D
Front Cell Neurosci 1662-5102
PMID : 31105531
Show abstract [+]
The neuronal serine protease tissue-type Plasminogen Activator (tPA) is an important player of the neuronal survival and of the synaptic plasticity. Thus, a better understanding the mechanisms regulating the neuronal trafficking of tPA is required to further understand how tPA can influence brain functions. Using confocal imaging including living cells and high-resolution cell imaging combined with an innovating labeling of tPA, we demonstrate that the neuronal tPA is contained in endosomal vesicles positives for Rabs and in exosomal vesicles positives for synaptobrevin-2 (VAMP2) in dendrites and axons. tPA-containing vesicles differ in their dynamics with the dendritic tPA containing-vesicles less mobile than the axonal tPA-containing vesicles, these laters displaying mainly a retrograde trafficking. Interestingly spontaneous exocytosis of tPA containing-vesicles occurs largely in dendrites.
Recent Advances in Nanomedicine for Ischemic and Hemorrhagic Stroke.
Bonnard T, Gauberti M, Martinez de Lizarrondo S, Campos F, Vivien D
Stroke 1524-4628
PMID : 30932782
KEYWORDS : Animals|Brain Ischemia|diagnosis|Humans|Intracranial Hemorrhages|diagnosis|Nanomedicine|methods|Stroke|diagnosis|Thrombolytic Therapy|methods
Tissue-Type Plasminogen Activator Controlled Corticogenesis Through a Mechanism Dependent of NMDA Receptors Expressed on Radial Glial Cells.
Pasquet N, Douceau S, Naveau M, Lesept F, Louessard M, Lebouvier L, Hommet Y, Vivien D, Bardou I
Cereb Cortex 1460-2199
PMID : 29878094
KEYWORDS : Animals|Cell Movement|physiology|Cerebral Cortex|embryology|Ependymoglial Cells|metabolism|Female|Male|Mice|Mice, Inbred C57BL|Mice, Knockout|Neurogenesis|physiology|Neurons|physiology|Receptors, N-Methyl-D-Aspartate|metabolism|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Modifications of neuronal migration during development, including processes that control cortical lamination are associated with functional deficits at adult stage. Here, we report for the first time that the lack of the serine protease tissue-type Plasminogen Activator (tPA), previously characterized as a neuromodulator and a gliotransmitter, leads to an altered cortical lamination in adult. This results in a neuronal migration defect of tPA deficient neurons which are stopped in the intermediate zone at E16. This phenotype is rescued by re-expressing a wild-type tPA in cortical neurons at E14 but not by a tPA that cannot interact with NMDAR. We thus hypothetized that the tPA produced by cortical neuronal progenitors can control their own radial migration through a mechanism dependent of NMDAR expressed at the surface of radial glial cells (RGC). Accordingly, conditional deletion of tPA in neuronal progenitors at E14 or overexpression of a dominant-negative NMDAR that cannot bind tPA in RGC also delayed neuronal migration. Moreover, the lack of tPA lead to an impaired maturation and orientation of RGC. These data provide the first demonstration that the neuronal serine protease tPA is an actor of a proper corticogenesis by its ability to control NMDAR signaling in RGC.
Reduced spinal cord parenchymal cerebrospinal fluid circulation in experimental autoimmune encephalomyelitis.
Fournier AP, Gauberti M, Quenault A, Vivien D, Macrez R, Docagne F
J Cereb Blood Flow Metab 1559-7016
PMID : 29376456
KEYWORDS : Animals|Brain|physiopathology|Cerebrospinal Fluid|physiology|Cisterna Magna|drug effects|Contrast Media|administration & dosage|Encephalomyelitis, Autoimmune, Experimental|physiopathology|Female|Indocyanine Green|administration & dosage|Magnetic Resonance Imaging|Meglumine|administration & dosage|Mice|Multiple Sclerosis|physiopathology|Organometallic Compounds|administration & dosage|Parenchymal Tissue|physiopathology|Spinal Cord|physiopathology
Show abstract [+]
An alteration of parenchymal cerebrospinal fluid circulation (CSF) has been proposed to take part in the pathophysiology of multiple sclerosis. By using an intragate T1-weighted high-resolution MRI of the spinal cord of freely breathing mice injected with a gadolinium chelate in the cisterna magna, we show that a parenchymal CSF circulation exists in the spinal cord, in addition to that originally described in the brain. In experimental autoimmune encephalomyelitis, a model of multiple sclerosis, we show a reduction of parenchymal CSF circulation specifically in the spinal cord but not in the brain.
2018
The Age-Well observational study on expert meditators in the Medit-Ageing European project.
Lutz A, Klimecki OM, Collette F, Poisnel G, Arenaza-Urquijo E, Marchant NL, De La Sayette V, Rauchs G, Salmon E, Vuilleumier P, Frison E, Vivien D, Chételat G,
Alzheimers Dement (N Y) 2352-8737
PMID : 30662933
Show abstract [+]
The Age-Well observational, cross-sectional study investigates the affective and cognitive mechanisms of meditation expertise with behavioral, neuroimaging, sleep, and biological measures sensitive to aging and Alzheimer's disease (AD).
The SCD-Well randomized controlled trial: Effects of a mindfulness-based intervention versus health education on mental health in patients with subjective cognitive decline (SCD).
Marchant NL, Barnhofer T, Klimecki OM, Poisnel G, Lutz A, Arenaza-Urquijo E, Collette F, Wirth M, Schild AK, Coll-Padrós N, Reyrolle L, Horney D, Krolak-Salmon P, Molinuevo JL, Walker Z, Maillard A, Frison E, Jessen F, Chételat G,
Alzheimers Dement (N Y) 2352-8737
PMID : 30581979
Show abstract [+]
Subjectively experienced cognitive decline in older adults is an indicator of increased risk for dementia and is also associated with increased levels of anxiety symptoms. As anxiety is itself emerging as a risk factor for cognitive decline and dementia, the primary question of the present study is whether an 8-week mindfulness-based intervention can significantly reduce anxiety symptoms in patients with subjective cognitive decline (SCD). The secondary questions pertain to whether such changes extend to other domains of psychological, social, and biological functioning (including cognition, self-regulation, lifestyle, well-being and quality of life, sleep, and selected blood-based biomarkers) associated with mental health, older age, and risk for dementia.
The Age-Well randomized controlled trial of the Medit-Ageing European project: Effect of meditation or foreign language training on brain and mental health in older adults.
Poisnel G, Arenaza-Urquijo E, Collette F, Klimecki OM, Marchant NL, Wirth M, de La Sayette V, Rauchs G, Salmon E, Vuilleumier P, Frison E, Maillard A, Vivien D, Lutz A, Chételat G,
Alzheimers Dement (N Y) 2352-8737
PMID : 30581977
Show abstract [+]
The Age-Well clinical trial is an ongoing monocentric, randomized, controlled trial aiming to assess an 18-month preventive meditation-based intervention directly targeting the attentional and emotional dimensions of aging to promote mental health and well-being in elderly people.
Ischemia-Reperfusion Injury After Endovascular Thrombectomy for Ischemic Stroke.
Gauberti M, Lapergue B, Martinez de Lizarrondo S, Vivien D, Richard S, Bracard S, Piotin M, Gory B
Stroke 1524-4628
PMID : 30571423
KEYWORDS : Aged|Aged, 80 and over|Brain Ischemia|surgery|Diffusion Magnetic Resonance Imaging|Disease Progression|Endovascular Procedures|Female|Humans|Male|Middle Aged|Postoperative Complications|diagnostic imaging|Reperfusion Injury|diagnostic imaging|Stroke|surgery|Thrombectomy
Show abstract [+]
Background and Purpose- In experimental models of ischemic stroke, abrupt reperfusion is associated with secondary brain damages, responsible for up to 70% of the final lesion size. Whether this remains true in humans is unknown. Methods- Using data from the ASTER randomized trial (Aspiration vs Stent Retriever for Successful Revascularization), we investigated the effect of complete reperfusion (defined as a modified Thrombolysis In Cerebral Infarction 3) after endovascular thrombectomy on early lesion growth as assessed by diffusion-weighted imaging at baseline and 1 day after reperfusion. Results- Among 381 patients included in the trial, 35 achieved complete reperfusion, benefited from both baseline and day 1 diffusion-weighted imaging, lacked significant hemorrhagic transformation, and were, therefore, included in the present study. We found that the median growth of the ischemic lesion between baseline and day 1 was only 0.9 mL after complete reperfusion, representing <4% of the mean lesion size. The actual lesion growth occurring after reperfusion is probably even smaller because this lesion growth occurred, at least in part, between baseline imaging and complete reperfusion, as demonstrated by a statistically significant positive correlation between imaging-to-reperfusion time and lesion growth ( R2=0.116; P=0.048). Conclusions- There is no significant lesion growth after complete reperfusion in most patients. This important discrepancy between clinical and preclinical pathophysiologies should be considered during preclinical evaluation of neuroprotective strategies.
The role of plasminogen activators in stroke treatment: fibrinolysis and beyond.
Thiebaut AM, Gauberti M, Ali C, Martinez De Lizarrondo S, Vivien D, Yepes M, Roussel BD
Lancet Neurol 1474-4465
PMID : 30507392
KEYWORDS : Animals|Fibrinolysis|drug effects|Humans|Stroke|therapy|Tissue Plasminogen Activator|pharmacology
Show abstract [+]
Although recent technical advances in thrombectomy have revolutionised acute stroke treatment, prevalence of disability and death related to stroke remain high. Therefore, plasminogen activators-eukaryotic, bacterial, or engineered forms that can promote fibrinolysis by converting plasminogen into active plasmin and facilitate clot breakdown-are still commonly used in the acute treatment of ischaemic stroke. Hence, plasminogen activators have become a crucial area for clinical investigation for their ability to recanalise occluded arteries in ischaemic stroke and to accelerate haematoma clearance in haemorrhagic stroke. However, inconsistent results, insufficient evidence of efficacy, or reports of side-effects in trial settings might reduce the use of plasminogen activators in clinical practice. Additionally, the mechanism of action for plasminogen activators could extend beyond the vessel lumen and involve plasminogen-independent processes, which would suggest that plasminogen activators have also non-fibrinolytic roles. Understanding the complex mechanisms of action of plasminogen activators can guide future directions for therapeutic interventions in patients with stroke.
Cerebrospinal fluid leakage after posterior fossa surgery may impair brain metabolite clearance.
Goulay R, Aron Badin R, Flament J, Emery E, Hantraye P, Vivien D, Gaberel T
Neurochirurgie 1773-0619
PMID : 30477647
KEYWORDS : Animals|Brain|metabolism|Cerebrospinal Fluid|drug effects|Cerebrospinal Fluid Rhinorrhea|etiology|Gadolinium|therapeutic use|Glymphatic System|surgery|Humans|Primates
Show abstract [+]
The discovery of the important role of cerebrospinal fluid (CSF) drainage of cerebral metabolite waste, known as the glymphatic system, has changed our view of brain waste clearance. We recently performed experiments to evaluate the glymphatic system in non-human primates (NHP). Here, we report the case of an NHP with iatrogenic CSF leakage. In this animal, solute transport through the brain, assessed by gadolinium injection in the CSF, was severely impaired by iatrogenic pseudomeningocele. This observation raises an important question: does brain surgery, and particularly posterior fossa surgery, lead to chronic impairment of parenchymal CSF circulation and solute transport?
A de novo variant in ADGRL2 suggests a novel mechanism underlying the previously undescribed association of extreme microcephaly with severely reduced sulcation and rhombencephalosynapsis.
Vezain M, Lecuyer M, Rubio M, Dupé V, Ratié L, David V, Pasquier L, Odent S, Coutant S, Tournier I, Trestard L, Adle-Biassette H, Vivien D, Frébourg T, Gonzalez BJ, Laquerrière A, Saugier-Veber P
Acta Neuropathol Commun 2051-5960
PMID : 30340542
KEYWORDS : Adult|Animals|Cell Cycle|genetics|Cells, Cultured|Chick Embryo|DNA Mutational Analysis|Embryo, Mammalian|Female|Fetus|Gene Expression Regulation, Developmental|genetics|Gestational Age|Humans|Male|Mice|Mice, Inbred C57BL|Mice, Transgenic|Microcephaly|complications|Middle Aged|Mutation|genetics|Neuroglia|metabolism|Receptors, G-Protein-Coupled|genetics|Rhombencephalon|diagnostic imaging
Show abstract [+]
Extreme microcephaly and rhombencephalosynapsis represent unusual pathological conditions, each of which occurs in isolation or in association with various other cerebral and or extracerebral anomalies. Unlike microcephaly for which several disease-causing genes have been identified with different modes of inheritance, the molecular bases of rhombencephalosynapsis remain unknown and rhombencephalosynapsis presents mainly as a sporadic condition consistent with de novo dominant variations. We report for the first time the association of extreme microcephaly with almost no sulcation and rhombencephalosynapsis in a fœtus for which comparative patient-parent exome sequencing strategy revealed a heterozygous de novo missense variant in the ADGRL2 gene. ADGRL2 encodes latrophilin 2, an adhesion G-protein-coupled receptor whose exogenous ligand is α-latrotoxin. Adgrl2 immunohistochemistry and in situ hybridization revealed expression in the telencephalon, mesencephalon and rhombencephalon of mouse and chicken embryos. In human brain embryos and fœtuses, Adgrl2 immunoreactivity was observed in the hemispheric and cerebellar germinal zones, the cortical plate, basal ganglia, pons and cerebellar cortex. Microfluorimetry experiments evaluating intracellular calcium release in response to α-latrotoxin binding showed significantly reduced cytosolic calcium release in the fœtus amniocytes vs amniocytes from age-matched control fœtuses and in HeLa cells transfected with mutant ADGRL2 cDNA vs wild-type construct. Embryonic lethality was also observed in constitutive Adgrl2-/- mice. In Adgrl2+/- mice, MRI studies revealed microcephaly and vermis hypoplasia. Cell adhesion and wound healing assays demonstrated that the variation increased cell adhesion properties and reduced cell motility. Furthermore, HeLa cells overexpressing mutant ADGRL2 displayed a highly developed cytoplasmic F-actin network related to cytoskeletal dynamic modulation. ADGRL2 is the first gene identified as being responsible for extreme microcephaly with rhombencephalosynapsis. Increased cell adhesion, reduced cell motility and cytoskeletal dynamic alterations induced by the variant therefore represent a new mechanism responsible for microcephaly.
Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxL strategies through Mcl-1 down-regulation.
Bonnefond ML, Florent R, Lenoir S, Lambert B, Abeilard E, Giffard F, Louis MH, Elie N, Briand M, Vivien D, Poulain L, Gauduchon P, N'Diaye M
Oncotarget 1949-2553
PMID : 30338034
Show abstract [+]
The anti-apoptotic proteins Bcl-xL and Mcl-1 have been identified to play a pivotal role in apoptosis resistance in ovarian cancer and constitute key targets for innovative therapeutic strategies. Although BH3-mimetics (i.e. ABT-737) potently inhibit Bcl-xL activity, targeting Mcl-1 remains a hurdle to the success of these strategies. Calcium signaling is profoundly remodeled during carcinogenesis and was reported to activate the signaling pathway controlling Mcl-1 expression. In this context, we investigated the effect of carboxyamidotriazole (CAI), a calcium channel inhibitor used in clinical trials, on Mcl-1 expression. CAI had an anti-proliferative effect on ovarian carcinoma cell lines and strongly down-regulated Mcl-1 expression. It inhibited store-operated calcium entry (SOCE) and Mcl-1 translation through mTORC1 deactivation. Moreover, it sensitized ovarian carcinoma cells to anti-Bcl-xL strategies as their combination elicited massive apoptosis. Its effect on mTORC1 and Mcl-1 was mimicked by the potent SOCE inhibitor, YM58483, which also triggered apoptosis when combined with ABT-737. As a whole, this study suggests that CAI sensitizes to anti-Bcl-xL strategies via its action on Mcl-1 translation and that modulation of SOCE could extend the therapeutic arsenal for treatment of ovarian carcinoma.
Anti-inflammatory treatments for stroke: from bench to bedside.
Drieu A, Levard D, Vivien D, Rubio M
Ther Adv Neurol Disord 1756-2856
PMID : 30083232
Show abstract [+]
So far, intravenous tissue-type plasminogen activator (tPA) and mechanical removal of arterial blood clot (thrombectomy) are the only available treatments for acute ischemic stroke. However, the short therapeutic window and the lack of specialized stroke unit care make the overall availability of both treatments limited. Additional agents to combine with tPA administration or thrombectomy to enhance efficacy and improve outcomes associated with stroke are needed. Stroke-induced inflammatory processes are a response to the tissue damage due to the absence of blood supply but have been proposed also as key contributors to all the stages of the ischemic stroke pathophysiology. Despite promising results in experimental studies, inflammation-modulating treatments have not yet been translated successfully into the clinical setting. This review will (a) describe the timing of the stroke immune pathophysiology; (b) detail the immune responses to stroke sift-through cell type; and
Cerebrospinal fluid flow increases from newborn to adult stages.
Di Palma C, Goulay R, Chagnot S, Martinez De Lizarrondo S, Anfray A, Salaun JP, Maubert E, Lechapt-Zalcman E, Andreiuolo F, Gakuba C, Emery E, Vivien D, Gauberti M, Gaberel T
Dev Neurobiol 1932-846X
PMID : 30027587
KEYWORDS : Adult|Animals|Animals, Newborn|cerebrospinal fluid|Biological Transport|physiology|Brain|metabolism|Cerebral Ventricles|physiology|Cerebrospinal Fluid|physiology|Humans|Magnetic Resonance Imaging|methods|Mice|Rats, Wistar
Show abstract [+]
Solute transport through the brain is of major importance for the clearance of toxic molecules and metabolites, and it plays key roles in the pathophysiology of the central nervous system. This solute transport notably depends on the cerebrospinal fluid (CSF) flow, which circulates in the subarachnoid spaces, the ventricles and the perivascular spaces. We hypothesized that the CSF flow may be different in the perinatal period compared to the adult period. Using in vivo magnetic resonance imaging (MRI) and near-infrared fluorescence imaging (NIRF), we assessed the dynamic of the CSF flow in rodents at different ages. By injecting a contrast agent into the CSF, we first used MRI to demonstrate that CSF flow gradually increases with age, with the adult pattern observed at P90. This observation was confirmed by NIRF, which revealed an increased CSF flow in P90 rats when compared with P4 rats not only at the surface of the brain but also deep in the brain structures. Lastly, we evaluated the exit routes of the CSF from the brain. We demonstrated that indocyanine green injected directly into the striatum spread throughout the parenchyma in adult rats, whereas it stayed at the injection point in P4 rats. Moreover, the ability of CSF to exit through the nasal mucosa was increased in the adult rodents. Our results provide evidence that the perinatal brain has nonoptimal CSF flow and exit and, thus, may have impaired clean-up capacity. © 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018.
Impact of Bradykinin Generation During Thrombolysis in Ischemic Stroke.
Gauberti M, Potzeha F, Vivien D, Martinez de Lizarrondo S
Front Med (Lausanne) 2296-858X
PMID : 30018956
Show abstract [+]
Ischemic stroke is one of the leading causes of death and disability worldwide. Current medical management in the acute phase is based on the activation of the fibrinolytic cascade by intravenous injection of a plasminogen activator (such as tissue-type plasminogen activator, tPA) that promotes restauration of the cerebral blood flow and improves stroke outcome. Unfortunately, the use of tPA is associated with deleterious effects such as hemorrhagic transformation, symptomatic brain edema, and angioedema, which limit the efficacy of this therapeutic strategy. Preclinical and clinical evidence suggests that intravenous thrombolysis generates large amounts of bradykinin, a peptide with potent pro-inflammatory, and pro-edematous effects. This tPA-triggered generation of bradykinin could participate in the deleterious effects of thrombolysis and is a potential target to improve neurological outcome in tPA-treated patients. The present review aims at summarizing current evidence linking thrombolysis, bradykinin generation, and neurovascular damage.
Erratum to: Molecular Magnetic Resonance Imaging (mMRI).
Gauberti M, Fournier AP, Vivien D, Martinez de Lizarrondo S
Methods Mol Biol 1940-6029
PMID : 29605882
Modification of apparent intracerebral hematoma volume on T2∗-weighted images during normobaric oxygen therapy may contribute to false diagnosis.
Goulay R, Drieu A, Di Palma C, Pro-Sistiaga P, Delcroix N, Chazalviel L, Saulnier R, Gakuba C, Goursaud S, Young AR, Gauberti M, Orset C, Emery E, Vivien D, Gaberel T
J Clin Neurosci 1532-2653
PMID : 29571939
KEYWORDS : Animals|Cerebral Hemorrhage|diagnostic imaging|Diagnostic Errors|Hematoma|diagnostic imaging|Magnetic Resonance Imaging|standards|Oxygen Inhalation Therapy|adverse effects|Swine
Show abstract [+]
It was previously reported that normobaric oxygen therapy (NBO) significantly affected T2∗-weighted imaging in a mouse model of intracerebral hemorrhage (ICH). However, it is unclear whether a similar phenomenon exists in large volume ICH as seen in human pathology. We investigated the effects of NBO on T2∗-weighted images in a pig model of ICH. Our data show that NBO makes disappear a peripheral crown of the hematoma, which in turn decreases the apparent volume of ICH by 18%. We hypothesized that this result could be translated to ICH in human, and subsequently could lead to inaccurate diagnostic.
Influence of on-going treatment with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker on the outcome of patients treated with intravenous rt-PA for ischemic stroke.
Gilliot S, Sibon I, Mas JL, Moulin T, Béjot Y, Cordonnier C, Giroud M, Odou P, Bordet R, Vivien D, Leys D,
J Neurol 1432-1459
PMID : 29549467
KEYWORDS : Administration, Intravenous|Aged|Aged, 80 and over|Angiotensin Receptor Antagonists|therapeutic use|Angiotensin-Converting Enzyme Inhibitors|therapeutic use|Brain Ischemia|complications|Female|Fibrinolytic Agents|therapeutic use|Follow-Up Studies|Humans|Intracranial Hemorrhages|complications|Male|Middle Aged|Prospective Studies|Recombinant Proteins|therapeutic use|Stroke|complications|Tissue Plasminogen Activator|therapeutic use|Treatment Outcome
Show abstract [+]
Many patients who receive intravenous (i.v.) recombinant tissue-plasminogen activator (rt-PA) for acute cerebral ischemia were under angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) at stroke onset. ACE-Is and ARBs have neuroprotective properties in animal models.
Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke.
Roth S, Singh V, Tiedt S, Schindler L, Huber G, Geerlof A, Antoine DJ, Anfray A, Orset C, Gauberti M, Fournier A, Holdt LM, Harris HE, Engelhardt B, Bianchi ME, Vivien D, Haffner C, Bernhagen J, Dichgans M, Liesz A
Sci Transl Med 1946-6242
PMID : 29540615
KEYWORDS : Alarmins|metabolism|Animals|Atherosclerosis|metabolism|Brain|metabolism|Immunity, Innate|physiology|Inflammation|metabolism|Mice|Plaque, Atherosclerotic|metabolism|Stroke|metabolism
Show abstract [+]
Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis-a major source of recurrent vascular events-have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)-signaling cascade and increased plaque load and vulnerability. Recruitment of activated monocytes via the CC-chemokine ligand 2-CC-chemokine receptor type 2 pathway was critical in stroke-induced vascular inflammation. Neutralization of circulating alarmins or knockdown of RAGE attenuated atheroprogression. Blockage of β3-adrenoreceptors attenuated the egress of myeloid monocytes after stroke, whereas neutralization of circulating alarmins was required to reduce systemic monocyte activation and aortic invasion. Our findings identify a synergistic effect of the sympathetic stress response and alarmin-driven inflammation via RAGE as a critical mechanism of exacerbated atheroprogression after stroke.
Molecular Magnetic Resonance Imaging of Endothelial Activation in the Central Nervous System.
Gauberti M, Fournier AP, Docagne F, Vivien D, Martinez de Lizarrondo S
Theranostics 1838-7640
PMID : 29507614
KEYWORDS : Animals|Central Nervous System|blood supply|Dextrans|chemistry|Endothelial Cells|metabolism|Humans|Magnetic Resonance Imaging|Magnetite Nanoparticles|chemistry|Molecular Imaging|Neurodegenerative Diseases|diagnostic imaging
Show abstract [+]
Endothelial cells of the central nervous system over-express surface proteins during neurological disorders, either as a cause, or a consequence, of the disease. Since the cerebral vasculature is easily accessible by large contrast-carrying particles, it constitutes a target of choice for molecular magnetic resonance imaging (MRI). In this review, we highlight the most recent advances in molecular MRI of brain endothelial activation and focus on the development of micro-sized particles of iron oxide (MPIO) targeting adhesion molecules including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), P-Selectin and E-Selectin. We also discuss the perspectives and challenges for the clinical application of this technology in neurovascular disorders (ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, diabetes mellitus), neuroinflammatory disorders (multiple sclerosis, brain infectious diseases, sepsis), neurodegenerative disorders (Alzheimer's disease, vascular dementia, aging) and brain cancers (primitive neoplasms, metastasis).
General Anesthesia Inhibits the Activity of the "Glymphatic System".
Gakuba C, Gaberel T, Goursaud S, Bourges J, Di Palma C, Quenault A, Martinez de Lizarrondo S, Vivien D, Gauberti M
Theranostics 1838-7640
PMID : 29344300
KEYWORDS : Anesthesia, General|adverse effects|Anesthetics, Inhalation|adverse effects|Animals|Contrast Media|pharmacokinetics|Fluorescent Dyes|pharmacokinetics|Glymphatic System|diagnostic imaging|Magnetic Resonance Imaging|methods|Male|Mice|Spectroscopy, Near-Infrared|methods
Show abstract [+]
According to the "glymphatic system" hypothesis, brain waste clearance is mediated by a continuous replacement of the interstitial milieu by a bulk flow of cerebrospinal fluid (CSF). Previous reports suggested that this cerebral CSF circulation is only active during general anesthesia or sleep, an effect mediated by the dilatation of the extracellular space. Given the controversies regarding the plausibility of this phenomenon and the limitations of currently available methods to image the glymphatic system, we developed original whole-brain in vivo imaging methods to investigate the effects of general anesthesia on the brain CSF circulation. We used magnetic resonance imaging (MRI) and near-infrared fluorescence imaging (NIRF) after injection of a paramagnetic contrast agent or a fluorescent dye in the cisterna magna, in order to investigate the impact of general anesthesia (isoflurane, ketamine or ketamine/xylazine) on the intracranial CSF circulation in mice. In vivo imaging allowed us to image CSF flow in awake and anesthetized mice and confirmed the existence of a brain-wide CSF circulation. Contrary to what was initially thought, we demonstrated that the parenchymal CSF circulation is mainly active during wakefulness and significantly impaired during general anesthesia. This effect was especially significant when high doses of anesthetic agent were used (3% isoflurane). These results were consistent across the different anesthesia regimens and imaging modalities. Moreover, we failed to detect a significant change in the brain extracellular water volume using diffusion weighted imaging in awake and anesthetized mice. The parenchymal diffusion of small molecular weight compounds from the CSF is active during wakefulness. General anesthesia has a negative impact on the intracranial CSF circulation, especially when using a high dose of anesthetic agent.
Molecular Magnetic Resonance Imaging (mMRI).
Gauberti M, Fournier AP, Vivien D, Martinez de Lizarrondo S
Methods Mol Biol 1940-6029
PMID : 29341017
KEYWORDS : Animals|Brain|metabolism|Contrast Media|Ferric Compounds|chemistry|Magnetic Resonance Imaging|methods|Mice|Molecular Imaging|methods|Vascular Cell Adhesion Molecule-1|metabolism
Show abstract [+]
Molecular magnetic resonance imaging (mMRI) enables the detection of a protein of interest in vivo, in a noninvasive manner. The general concept of mMRI is to target a contrast agent to a protein of interest, and to perform a contrast-sensitive MRI sequence. Typically, contrast agents are made of a "contrastophore" (the part of the construct responsible for the contrast on the images) and a targeting moiety ("pharmacophore"). Recently, the development of a new family of contrastophore carrying a high payload of iron oxide (micro-sized particles of iron oxide, MPIO) has led to a dramatic increase in the sensitivity of mMRI. Here, we describe the production of targeted MPIO using commercially available reagents and the MRI protocols to allow their detection in vivo.
Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors.
Iglesias-Rey R, Rodríguez-Yáñez M, Rodríguez-Castro E, Pumar JM, Arias S, Santamaría M, López-Dequidt I, Hervella P, Correa-Paz C, Sobrino T, Vivien D, Campos F, Castellanos M, Castillo J
Transl Stroke Res 1868-601X
PMID : 29116527
KEYWORDS : Aged|Aged, 80 and over|Cohort Studies|Female|Fibrinolytic Agents|adverse effects|Hemorrhage|chemically induced|Humans|Male|Middle Aged|ROC Curve|Reperfusion|Stroke|drug therapy|Tissue Plasminogen Activator|adverse effects|Treatment Outcome
Show abstract [+]
Based on preclinical studies suggesting that recombinant tissue plasminogen activator (rt-PA) may promote ischemic brain injuries, we investigated in patients the possible risk of worse clinical outcome after rt-PA treatment as a result of its inability to resolve cerebral ischemia. Here, we designed a cohort study using a retrospective analysis of patients who received treatment with intravenous (4.5-h window) or intraarterial rt-PA, without or with thrombectomy. Controls were consecutive patients who did not receive recanalization treatment, who met all inclusion criteria. As a marker of reperfusion, we defined the variable of early neurological improvement as the difference between the score of the National Institute of Health Stroke Scale (NIHSS) (at admission and 24 h). The main variable was worsening of the patient's functional situation in the first 3 months. To compare quantitative variables, we used Student's t test or the Mann-Whitney test. To estimate the odds ratios of each independent variable in the patient's worsening in the first 3 months, we used a logistic regression model. We included 1154 patients; 577 received rt-PA, and 577 served as controls. In the group of patients treated with rt-PA, 39.4% who did not present clinical reperfusion data developed worsening within 3 months after stroke compared with 3.5% of patients with reperfusion (P < 0.0001). These differences were not significant in the control group. In summary, administration of rt-PA intravenously or intraarterially without reperfusion within the first 24 h may be associated with a higher risk of functional deterioration in the first 3 months.
Optimized tPA: A non-neurotoxic fibrinolytic agent for the drainage of intracerebral hemorrhages.
Goulay R, Naveau M, Gaberel T, Vivien D, Parcq J
J Cereb Blood Flow Metab 1559-7016
PMID : 28741405
KEYWORDS : Animals|Brain Edema|drug therapy|Cerebral Hemorrhage|drug therapy|Clinical Trials, Phase III as Topic|Disease Models, Animal|Drug Evaluation, Preclinical|Fibrinolytic Agents|pharmacology|Humans|Male|Mice|Protein Engineering|Recombinant Proteins|genetics|Swine|Tissue Plasminogen Activator|genetics
Show abstract [+]
Intracerebral hemorrhage (ICH) is the most severe form of stroke. Catheter-delivered thrombolysis with recombinant tissue-type plasminogen activator (rtPA) for the drainage of ICH is currently under evaluation in a phase III clinical trial (MISTIE III). However, in a pig model of ICH, in situ fibrinolysis with rtPA was reported to increase peri-lesional edema by promoting N-methyl-D-aspartate (NMDA)-dependent excitotoxicity. In the present study, we engineered a non-neurotoxic tPA variant, OptPA, and investigated its safety and efficacy for in situ fibrinolysis in a rat model of ICH. Magnetic resonance imaging analyses of hematoma and edema volumes, behavioral tasks and histological analyses were performed to measure the effects of treatments. In vitro, OptPA was equally fibrinolytic as rtPA without promoting NMDA-dependent neurotoxicity. In vivo, in situ fibrinolysis using OptPA reduced hematoma volume, like rtPA, but it also reduced the evolution of peri-hematomal neuronal death and subsequent edema progression. Overall, this preclinical study demonstrates beneficial effects of OptPA compared to rtPA for the drainage of ICH.
Extracellular Matrix Modulation Is Driven by Experience-Dependent Plasticity During Stroke Recovery.
Quattromani MJ, Pruvost M, Guerreiro C, Backlund F, Englund E, Aspberg A, Jaworski T, Hakon J, Ruscher K, Kaczmarek L, Vivien D, Wieloch T
Mol Neurobiol 1559-1182
PMID : 28290150
KEYWORDS : Aged|Aged, 80 and over|Animals|Environment|Extracellular Matrix|metabolism|Female|Humans|Inflammation Mediators|metabolism|Male|Middle Aged|Neuronal Plasticity|physiology|Rats|Recovery of Function|physiology|Stroke|metabolism|Stroke Rehabilitation|methods
Show abstract [+]
Following stroke, complete cellular death in the ischemic brain area may ensue, with remaining brain areas undergoing tissue remodelling to various degrees. Experience-dependent brain plasticity exerted through an enriched environment (EE) promotes remodelling after central nervous system injury, such as stroke. Post-stroke tissue reorganization is modulated by growth inhibitory molecules differentially expressed within the ischemic hemisphere, like chondroitin sulfate proteoglycans found in perineuronal nets (PNNs). PNNs in the neocortex predominantly enwrap parvalbumin-containing GABAergic (PV/GABA) neurons, important in sensori-information processing. Here, we investigate how extracellular matrix (ECM) proteases and their inhibitors may participate in the regulation of PNN integrity during stroke recovery. Rats were subjected to photothrombotic stroke in the motor cortex, and functional deficits were assessed at 7 days of recovery. Sham and stroked rats were housed in either standard or EE conditions for 5 days, and infarct volumes were calculated. PNNs were visualized by immunohistochemistry and counted in the somatosensory cortex of both hemispheres. mRNA expression levels of ECM proteases and protease inhibitors were assessed by RT-qPCR and their activity analyzed by gel zymography. PNNs and protease activity were also studied in brains from stroke patients where similar results were observed. EE starting 2 days after stroke and continuing for 5 days stimulated behavioral recovery of limb-placement ability without affecting infarct size. EE promoted a decrease of PNNs around PV/GABA neurons and a concomitant modulation of the proteolytic activity and mRNA expression of ECM proteases and protease inhibitors in the somatosensory cortex. This study provides molecular targets for novel therapies that could support rehabilitation of stroke patients.
2017
ADAMTS-4 in oligodendrocytes contributes to myelination with an impact on motor function.
Pruvost M, Lépine M, Leonetti C, Etard O, Naveau M, Agin V, Docagne F, Maubert E, Ali C, Emery E, Vivien D
Glia 1098-1136
PMID : 28850711
KEYWORDS : ADAMTS4 Protein|genetics|Animals|Animals, Newborn|Calcium-Binding Proteins|metabolism|Corpus Callosum|metabolism|Disease Models, Animal|Evoked Potentials, Somatosensory|genetics|Gait Disorders, Neurologic|etiology|Locomotion|genetics|Male|Mice|Mice, Transgenic|Microfilament Proteins|metabolism|Microscopy, Electron|Movement Disorders|genetics|Myelin Basic Protein|metabolism|Nerve Tissue Proteins|metabolism|Oligodendroglia|metabolism|Receptor, Platelet-Derived Growth Factor alpha|metabolism|Statistics, Nonparametric|beta-Galactosidase|genetics
Show abstract [+]
Myelination is a late developmental process regulated by a set of inhibitory and stimulatory factors, including extracellular matrix components. Accordingly, chondroitin sulfate proteoglycans (CSPGs) act as negative regulators of myelination processes. A disintegrin and metalloproteinase with thrombospondin motifs type 4 (ADAMTS-4) is an extracellular protease capable of degrading CSPGs. Although exogenous ADAMTS-4 has been proven to be beneficial in several models of central nervous system (CNS) injuries, the physiological functions of endogenous ADAMTS-4 remain poorly understood. We first used Adamts4/LacZ reporter mice to reveal that ADAMTS-4 is strongly expressed in the CNS, especially in the white matter, with a cellular profile restricted to mature oligodendrocytes. Interestingly, we evidenced an abnormal myelination in Adamts4-/- mice, characterized by a higher diameter of myelinated axons with a shifting g-ratio. Accordingly, lack of ADAMTS-4 is accompanied by motor deficits and disturbed nervous electrical activity. In conclusion, we demonstrate that ADAMTS-4 is a new marker of mature oligodendrocytes contributing to the myelination processes and thus to the control of motor capacities.
Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration.
Vaur P, Brugg B, Mericskay M, Li Z, Schmidt MS, Vivien D, Orset C, Jacotot E, Brenner C, Duplus E
FASEB J 1530-6860
PMID : 28842432
KEYWORDS : Animals|Axons|drug effects|Cell Death|drug effects|Cells, Cultured|Male|Mice|Mice, Inbred C57BL|Mice, Knockout|N-Methylaspartate|pharmacology|Neurons|drug effects|Neuroprotective Agents|pharmacology|Niacinamide|analogs & derivatives|Pyridinium Compounds|Real-Time Polymerase Chain Reaction
Show abstract [+]
NAD+ depletion is a common phenomenon in neurodegenerative pathologies. Excitotoxicity occurs in multiple neurologic disorders and NAD+ was shown to prevent neuronal degeneration in this process through mechanisms that remained to be determined. The activity of nicotinamide riboside (NR) in neuroprotective models and the recent description of extracellular conversion of NAD+ to NR prompted us to probe the effects of NAD+ and NR in protection against excitotoxicity. Here, we show that intracortical administration of NR but not NAD+ reduces brain damage induced by NMDA injection. Using cortical neurons, we found that provision of extracellular NR delays NMDA-induced axonal degeneration (AxD) much more strongly than extracellular NAD+ Moreover, the stronger effect of NR compared to NAD+ depends of axonal stress since in AxD induced by pharmacological inhibition of nicotinamide salvage, both NAD+ and NR prevent neuronal death and AxD in a manner that depends on internalization of NR. Taken together, our findings demonstrate that NR is a better neuroprotective agent than NAD+ in excitotoxicity-induced AxD and that axonal protection involves defending intracellular NAD+ homeostasis.-Vaur, P., Brugg, B., Mericskay, M., Li, Z., Schmidt, M. S., Vivien, D., Orset, C., Jacotot, E., Brenner, C., Duplus, E. Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration.
Experimental and clinical evidence of differential effects of magnesium sulfate on neuroprotection and angiogenesis in the fetal brain.
Lecuyer M, Rubio M, Chollat C, Lecointre M, Jégou S, Leroux P, Cleren C, Leroux-Nicollet I, Marpeau L, Vivien D, Marret S, Gonzalez BJ
Pharmacol Res Perspect 2052-1707
PMID : 28805973
Show abstract [+]
Clinical studies showed beneficial effects of magnesium sulfate regarding the risk of cerebral palsy. However, regimen protocols fluctuate worldwide and risks of adverse effects impacting the vascular system have been reported for human neonates, keeping open the question of the optimal dosing. Using clinically relevant concentrations and doses of magnesium sulfate, experiments consisted of characterizing, respectively, ex vivo and in vivo, the effects of magnesium sulfate on the nervous and vascular systems of mouse neonates by targeting neuroprotection, angiogenesis, and hemodynamic factors and in measuring, in human fetuses, the impact of a 4-g neuroprotective loading dose of magnesium sulfate on brain hemodynamic parameters. Preclinical experiments using cultured cortical slices from mouse neonates showed that the lowest and highest tested concentrations of magnesium sulfate were equally potent to prevent excitotoxic-induced cell death, cell edema, cell burst, and intracellular calcium increase, whereas no side effects were found regarding apoptosis. In contrast, in vivo data revealed that magnesium sulfate exerted dose-dependent vascular effects on the fetal brain. In particular, it induced brain hypoperfusion, stabilization of Hif-1α, long-term upregulation of VEGF-R2 expression, impaired endothelial viability, and altered cortical angiogenesis. Clinically, in contrast to 6-g loading doses used in some protocols, a 4-g bolus of magnesium sulfate did not altered fetal brain hemodynamic parameters. In conclusion, these data provide the first mechanistic evidence of double-sword and dose-dependent actions of magnesium sulfate on nervous and vascular systems. They strongly support the clinical use of neuroprotection protocols validated for the lowest (4-g) loading dose of magnesium sulfate.
Can the benefits of rtPA treatment for stroke be improved?
Vivien D
Rev Neurol (Paris) 0035-3787
PMID : 28797689
KEYWORDS : Humans|Plasminogen Activators|therapeutic use|Stroke|drug therapy|Thrombectomy|Tissue Plasminogen Activator|therapeutic use
Show abstract [+]
Tissue-type plasminogen activator (tPA) is a serine protease well known to promote fibrinolysis. This is why: its recombinant form (rtPA) can be used, either alone or combined with thrombectomy, to promote recanalization/reperfusion following ischemic stroke. However, its overall benefits are counteracted by some of its side-effects, including incomplete lysis of clots, an increased risk of hemorrhagic transformation and the possibility of neurotoxicity. Nevertheless, better understanding of the mechanisms by which tPA influences brain function and promotes its alteration may help in the design of new strategies to improve stroke therapy.
The choroid plexus is a key cerebral invasion route for T cells after stroke.
Llovera G, Benakis C, Enzmann G, Cai R, Arzberger T, Ghasemigharagoz A, Mao X, Malik R, Lazarevic I, Liebscher S, Ertürk A, Meissner L, Vivien D, Haffner C, Plesnila N, Montaner J, Engelhardt B, Liesz A
Acta Neuropathol 1432-0533
PMID : 28762187
KEYWORDS : Aged|Aged, 80 and over|Animals|Brain Injuries, Traumatic|pathology|Brain Ischemia|pathology|Cell Movement|physiology|Cerebral Cortex|pathology|Chemokine CCL2|metabolism|Choroid Plexus|pathology|Disease Models, Animal|Female|Humans|Male|Mice, Inbred C57BL|Mice, Transgenic|Myeloid Cells|pathology|Stroke|pathology|T-Lymphocytes|pathology
Show abstract [+]
Neuroinflammation contributes substantially to stroke pathophysiology. Cerebral invasion of peripheral leukocytes-particularly T cells-has been shown to be a key event promoting inflammatory tissue damage after stroke. While previous research has focused on the vascular invasion of T cells into the ischemic brain, the choroid plexus (ChP) as an alternative cerebral T-cell invasion route after stroke has not been investigated. We here report specific accumulation of T cells in the peri-infarct cortex and detection of T cells as the predominant population in the ipsilateral ChP in mice as well as in human post-stroke autopsy samples. T-cell migration from the ChP to the peri-infarct cortex was confirmed by in vivo cell tracking of photoactivated T cells. In turn, significantly less T cells invaded the ischemic brain after photothrombotic lesion of the ipsilateral ChP and in a stroke model encompassing ChP ischemia. We detected a gradient of CCR2 ligands as the potential driving force and characterized the neuroanatomical pathway for the intracerebral migration. In summary, our study demonstrates that the ChP is a key invasion route for post-stroke cerebral T-cell invasion and describes a CCR2-ligand gradient between cortex and ChP as the potential driving mechanism for this invasion route.
Vascular Tissue-Type Plasminogen Activator Promotes Intracranial Aneurysm Formation.
Labeyrie PE, Goulay R, Martinez de Lizarrondo S, Hébert M, Gauberti M, Maubert E, Delaunay B, Gory B, Signorelli F, Turjman F, Touzé E, Courthéoux P, Vivien D, Orset C
Stroke 1524-4628
PMID : 28754830
KEYWORDS : Adult|Aneurysm, Ruptured|diagnostic imaging|Animals|Female|Fluorescent Antibody Technique|Humans|Immunohistochemistry|Intracranial Aneurysm|diagnostic imaging|Magnetic Resonance Imaging|Mice|Mice, Knockout|Plasminogen Activator Inhibitor 1|genetics|Rupture, Spontaneous|Tissue Plasminogen Activator|genetics
Show abstract [+]
Although the mechanisms that contribute to intracranial aneurysm (IA) formation and rupture are not totally elucidated, inflammation and matrix remodeling are incriminated. Because tPA (tissue-type plasminogen activator) controls both inflammatory and matrix remodeling processes, we hypothesized that tPA could be involved in the pathophysiology of IA.
Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death.
Louessard M, Bardou I, Lemarchand E, Thiebaut AM, Parcq J, Leprince J, Terrisse A, Carraro V, Fafournoux P, Bruhat A, Orset C, Vivien D, Ali C, Roussel BD
Cell Death Differ 1476-5403
PMID : 28644439
KEYWORDS : Activating Transcription Factor 4|metabolism|Animals|Apoptosis|drug effects|Cell Death|drug effects|Endoplasmic Reticulum Chaperone BiP|Endoplasmic Reticulum Stress|drug effects|Fibrinolytic Agents|pharmacology|Heat-Shock Proteins|metabolism|Mice|Neurons|cytology|Protein Serine-Threonine Kinases|metabolism|Signal Transduction|drug effects|Thromboembolism|therapy|Tissue Plasminogen Activator|pharmacology|Unfolded Protein Response|drug effects
Show abstract [+]
The unfolded protein response (UPR) is an endoplasmic reticulum (ER) -related stress conserved pathway that aims to protect cells from being overwhelmed. However, when prolonged, UPR activation converts to a death signal, which relies on its PERK-eIF2α branch. Overactivation of the UPR has been implicated in many neurological diseases, including cerebral ischaemia. Here, by using an in vivo thromboembolic model of stroke on transgenic ER stress-reporter mice and neuronal in vitro models of ischaemia, we demonstrate that ischaemic stress leads to the deleterious activation of the PERK branch of the UPR. Moreover, we show that the serine protease tissue-type plasminogen activator (tPA) can bind to cell surface Grp78 (78 kD glucose-regulated protein), leading to a decrease of the PERK pathway activation, thus a decrease of the deleterious factor CHOP, and finally promotes neuroprotection. Altogether, this work highlights a new role and a therapeutic potential of the chaperone protein Grp78 as a membrane receptor of tPA capable to prevent from ER stress overactivation.
Are Distal and Proximal Visual Cues Equally Important during Spatial Learning in Mice? A Pilot Study of Overshadowing in the Spatial Domain.
Hébert M, Bulla J, Vivien D, Agin V
Front Behav Neurosci 1662-5153
PMID : 28634446
Show abstract [+]
Animals use distal and proximal visual cues to accurately navigate in their environment, with the possibility of the occurrence of associative mechanisms such as cue competition as previously reported in honey-bees, rats, birds and humans. In this pilot study, we investigated one of the most common forms of cue competition, namely the overshadowing effect, between visual landmarks during spatial learning in mice. To this end, C57BL/6J × Sv129 mice were given a two-trial place recognition task in a T-maze, based on a novelty free-choice exploration paradigm previously developed to study spatial memory in rodents. As this procedure implies the use of different aspects of the environment to navigate (i.e., mice can perceive from each arm of the maze), we manipulated the distal and proximal visual landmarks during both the acquisition and retrieval phases. Our prospective findings provide a first set of clues in favor of the occurrence of an overshadowing between visual cues during a spatial learning task in mice when both types of cues are of the same modality but at varying distances from the goal. In addition, the observed overshadowing seems to be non-reciprocal, as distal visual cues tend to overshadow the proximal ones when competition occurs, but not vice versa. The results of the present study offer a first insight about the occurrence of associative mechanisms during spatial learning in mice, and may open the way to promising new investigations in this area of research. Furthermore, the methodology used in this study brings a new, useful and easy-to-use tool for the investigation of perceptive, cognitive and/or attentional deficits in rodents.
Prediction of disease activity in models of multiple sclerosis by molecular magnetic resonance imaging of P-selectin.
Fournier AP, Quenault A, Martinez de Lizarrondo S, Gauberti M, Defer G, Vivien D, Docagne F, Macrez R
Proc Natl Acad Sci U S A 1091-6490
PMID : 28533365
KEYWORDS : Animals|Blood-Brain Barrier|diagnostic imaging|Brain|pathology|Contrast Media|Disease Models, Animal|Disease Progression|Encephalomyelitis, Autoimmune, Experimental|pathology|Magnetic Resonance Imaging|methods|Male|Mice|Mice, Inbred C57BL|Multiple Sclerosis|diagnostic imaging|P-Selectin|metabolism|Recurrence|Spinal Cord|pathology
Show abstract [+]
New strategies for detecting disease activity in multiple sclerosis are being investigated to ameliorate diagnosis and follow-up of patients. Today, although magnetic resonance imaging (MRI) is widely used to diagnose and monitor multiple sclerosis, no imaging tools exist to predict the evolution of disease and the efficacy of therapeutic strategies. Here, we show that molecular MRI targeting the endothelial adhesion molecule P-selectin unmasks the pathological events that take place in the spinal cord of mice subjected to chronic or relapsing experimental autoimmune encephalomyelitis. This approach provides a quantitative spatiotemporal follow-up of disease course in relation to clinical manifestations. Moreover, it predicts relapse in asymptomatic mice and remission in symptomatic animals. Future molecular MRI targeting P-selectin may be used to improve diagnosis, follow-up of treatment, and management of relapse/remission cycles in multiple sclerosis patients by providing information currently inaccessible through conventional MRI techniques.
Subarachnoid Hemorrhage Severely Impairs Brain Parenchymal Cerebrospinal Fluid Circulation in Nonhuman Primate.
Goulay R, Flament J, Gauberti M, Naveau M, Pasquet N, Gakuba C, Emery E, Hantraye P, Vivien D, Aron-Badin R, Gaberel T
Stroke 1524-4628
PMID : 28526764
KEYWORDS : Animals|Brain|diagnostic imaging|Cerebrovascular Circulation|physiology|Macaca fascicularis|Male|Parenchymal Tissue|diagnostic imaging|Primates|Severity of Illness Index|Subarachnoid Hemorrhage|cerebrospinal fluid
Show abstract [+]
Subarachnoid hemorrhage (SAH) is a devastating form of stroke with neurological outcomes dependent on the occurrence of delayed cerebral ischemia. It has been shown in rodents that some of the mechanisms leading to delayed cerebral ischemia are related to a decreased circulation of the cerebrospinal fluid (CSF) within the brain parenchyma. Here, we evaluated the cerebral circulation of the CSF in a nonhuman primate in physiological condition and after SAH.
Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi.
Martinez de Lizarrondo S, Gakuba C, Herbig BA, Repessé Y, Ali C, Denis CV, Lenting PJ, Touzé E, Diamond SL, Vivien D, Gauberti M
Circulation 1524-4539
PMID : 28487393
KEYWORDS : Acetylcysteine|pharmacology|Animals|Blood Platelets|cytology|Chlorides|toxicity|Disease Models, Animal|Ferric Compounds|toxicity|Fibrinolytic Agents|pharmacology|Infarction, Middle Cerebral Artery|drug therapy|Male|Mice|Platelet Aggregation|drug effects|Ristocetin|pharmacology|Thromboembolism|chemically induced|Thrombosis|prevention & control|Tissue Plasminogen Activator|therapeutic use|von Willebrand Factor|chemistry
Show abstract [+]
Platelet cross-linking during arterial thrombosis involves von Willebrand Factor (VWF) multimers. Therefore, proteolysis of VWF appears promising to disaggregate platelet-rich thrombi and restore vessel patency in acute thrombotic disorders such as ischemic stroke, acute coronary syndrome, or acute limb ischemia. N-Acetylcysteine (NAC, a clinically approved mucolytic drug) can reduce intrachain disulfide bonds in large polymeric proteins. In the present study, we postulated that NAC might cleave the VWF multimers inside occlusive thrombi, thereby leading to their dissolution and arterial recanalization.
Astrocytes regulate the balance between plasminogen activation and plasmin clearance via cell-surface actin.
Briens A, Bardou I, Lebas H, Miles LA, Parmer RJ, Vivien D, Docagne F
Cell Discov 2056-5968
PMID : 28417010
Show abstract [+]
Plasminogen activation is involved in many processes within the central nervous system, including synaptic plasticity, neuroinflammation and neurodegeneration. However, the mechanisms that regulate plasminogen activation in the brain still remain unknown. Here we demonstrate that astrocytes participate in this regulation by two mechanisms. First, the astrocyte plasma membrane serves as a surface for plasminogen activation by tissue-type plasminogen activator. This activation triggers downstream plasmin-dependent processes with important impacts in brain health and disease, such as fibrinolysis and brain-derived neurotrophic factor conversion. Second, astrocytes take up plasminogen and plasmin in a regulated manner through a novel mechanism involving endocytosis mediated by cell-surface actin and triggered by extracellular plasmin activity at the surface of astrocytes. Following endocytosis, plasminogen and plasmin are targeted to lysosomes for degradation. Thus, cell-surface actin acts as a sensor of plasmin activity to induce a negative feedback through plasmin endocytosis. This study provides evidence that astrocytes control the balance between plasmin formation and plasmin elimination in the brain parenchyma.
New thrombolytic strategy providing neuroprotection in experimental ischemic stroke: MMP10 alone or in combination with tissue-type plasminogen activator.
Roncal C, Martinez de Lizarrondo S, Salicio A, Chevilley A, Rodriguez JA, Rosell A, Couraud PO, Weksler B, Montaner J, Vivien D, Páramo JA, Orbe J
Cardiovasc Res 1755-3245
PMID : 28379489
KEYWORDS : Animals|Behavior, Animal|drug effects|Brain|drug effects|Calcium Signaling|drug effects|Capillary Permeability|drug effects|Cell Survival|drug effects|Cells, Cultured|Claudin-5|metabolism|Disease Models, Animal|Drug Therapy, Combination|Electric Impedance|Endothelial Cells|drug effects|Fibrinolytic Agents|administration & dosage|Humans|Infarction, Middle Cerebral Artery|metabolism|Male|Matrix Metalloproteinase 10|administration & dosage|Mice, Inbred C57BL|Mitogen-Activated Protein Kinase 1|metabolism|Mitogen-Activated Protein Kinase 3|metabolism|Motor Activity|drug effects|Neurons|drug effects|Neuroprotective Agents|administration & dosage|Thrombolytic Therapy|adverse effects|Time Factors|Tissue Plasminogen Activator|administration & dosage
Show abstract [+]
Early reperfusion with tissue-type plasminogen activator (tPA) is an effective therapeutic strategy to treat acute ischemic stroke, but only 1/3 of tPA-treated patients recover and are free from disability. tPA has also shown neurotoxicity in experimental models of cerebral ischemia. Considering that MMP-10 improves stroke injury, we have examined the therapeutic and protective effect of MMP10 and tPA/MMP10 as clot-dissolving and neuroprotective agent in an experimental model of ischemic stroke and studied in vitro the molecular pathways involved in MMP10-mediated effects.
Tissue-type plasminogen activator exerts EGF-like chemokinetic effects on oligodendrocytes in white matter (re)myelination.
Leonetti C, Macrez R, Pruvost M, Hommet Y, Bronsard J, Fournier A, Perrigault M, Machin I, Vivien D, Clemente D, De Castro F, Maubert E, Docagne F
Mol Neurodegener 1750-1326
PMID : 28231842
KEYWORDS : Animals|Brain Injuries|pathology|Cell Differentiation|drug effects|Cell Movement|drug effects|Central Nervous System|drug effects|Corpus Callosum|drug effects|Embryo, Mammalian|Epidermal Growth Factor|Imaging, Three-Dimensional|Immunoblotting|Immunohistochemistry|Magnetic Resonance Imaging|Mice|Mice, Inbred C57BL|Mice, Knockout|Myelin Sheath|drug effects|Neural Stem Cells|cytology|Oligodendroglia|cytology|Tissue Plasminogen Activator|pharmacology|White Matter|drug effects
Show abstract [+]
The ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation. Tissue plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS), where it regulates cell fate. In particular, tPA has been reported to protect oligodendrocytes from apoptosis and to facilitate the migration of neurons. Here, we investigated whether tPA can also participate in the migration of OPCs during CNS development and during remyelination after focal white matter lesion.
ADAMTS-4 in central nervous system pathologies.
Lemarchant S, Wojciechowski S, Vivien D, Koistinaho J
J Neurosci Res 1097-4547
PMID : 28084617
KEYWORDS : ADAMTS4 Protein|Animals|Central Nervous System Diseases|metabolism|Humans
Show abstract [+]
ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs type 4) is a metalloproteinase specialized in the degradation of chondroitin sulfate proteoglycans, contributing to cartilage breakdown during arthritis. In this review, we first focus on the modifications of ADAMTS-4 expression during CNS physiological and pathological conditions, including chronic diseases and injuries. Then, we discuss the contributions of ADAMTS-4 to mechanisms mediating neuroplasticity, neuroinflammation and neurodegeneration during spinal cord injury, ischemic stroke, amyotrophic lateral sclerosis and Alzheimer's disease. Here, we provide an overview of ADAMTS-4 functions and effects in the CNS, and we discuss directions for future studies and treatments. Overall, this review highlights that ADAMTS-4 is a unique multifaceted metalloproteinase which influences various CNS disease pathophysiologies. © 2017 Wiley Periodicals, Inc.
Lack of collagen XV is protective after ischemic stroke in mice.
Dhungana H, Huuskonen MT, Pihlajaniemi T, Heljasvaara R, Vivien D, Kanninen KM, Malm T, Koistinaho J, Lemarchant S
Cell Death Dis 2041-4889
PMID : 28079884
KEYWORDS : Animals|Brain Ischemia|genetics|Cerebral Cortex|metabolism|Collagen|genetics|Disease Models, Animal|Humans|Mice|Mice, Knockout|Neuroprotection|genetics|Stroke|genetics|Tissue Engineering|Tissue Plasminogen Activator|administration & dosage|Tissue Scaffolds|Vascular Endothelial Growth Factor A|genetics
Show abstract [+]
Collagens are key structural components of basement membranes, providing a scaffold for other components or adhering cells. Collagens and collagen-derived active fragments contribute to biological activities such as cell growth, differentiation and migration. Here, we report that collagen XV knock-out (ColXV KO) mice are resistant to experimental ischemic stroke. Interestingly, the infarcts of ColXV KO mice were as small as those of wild-type (WT) mice thrombolysed with recombinant tissue plasminogen activator (rtPA), the actual treatment for ischemic stroke. Importantly, there were no differences in the architecture of cerebrovascular anatomy between WT and ColXV KO mice. We found a twofold increase of the most potent pro-angiogenic factor, type A vascular growth endothelial factor (VEGF-A) in the ipsilateral cortex of rtPA-treated ischemic WT mice compared with untreated ischemic and sham-operated counterparts. A similar increase of VEGF-A was also found in both rtPA and untreated ischemic ColXV KO mice compared with sham ColXV KO mice. Finally, we evidenced that the levels of ColXV were increased in the plasma of WT mice treated with rtPA compared with untreated ischemic counterparts. Altogether, this study indicates that the lack ColXV is protective after stroke and that the degradation of endothelial ColXV may contribute to the beneficial effect of rtPA after ischemic stroke. The neuroprotection observed in ColXV KO mice may be attributed to the increased VEGF-A production following stroke in the ischemic territory.
Recent progress in translational research on neurovascular and neurodegenerative disorders.
Demuth HU, Dijkhuizen RM, Farr TD, Gelderblom M, Horsburgh K, Iadecola C, Mcleod DD, Michalski D, Murphy TH, Orbe J, Otte WM, Petzold GC, Plesnila N, Reiser G, Reymann KG, Rueger MA, Saur D, Savitz SI, Schilling S, Spratt NJ, Turner RJ, Vemuganti R, Vivien D, Yepes M, Zille M, Boltze J,
Restor Neurol Neurosci 1878-3627
PMID : 28059802
KEYWORDS : Animals|Cerebrovascular Disorders|diagnosis|Humans|Neurodegenerative Diseases|diagnosis|Translational Research, Biomedical
Show abstract [+]
The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient's outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms.This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations.
Molecular magnetic resonance imaging discloses endothelial activation after transient ischaemic attack.
Quenault A, Martinez de Lizarrondo S, Etard O, Gauberti M, Orset C, Haelewyn B, Segal HC, Rothwell PM, Vivien D, Touzé E, Ali C
Brain 1460-2156
PMID : 28031221
KEYWORDS : Animals|Biomarkers|metabolism|Disease Models, Animal|Endothelial Cells|Ischemic Attack, Transient|diagnostic imaging|Magnetic Resonance Imaging|methods|Male|Mice|Molecular Imaging|methods|P-Selectin|metabolism|Stroke|diagnostic imaging
Show abstract [+]
SEE SUN ET AL DOI101093/AWW306 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: About 20% of patients with ischaemic stroke have a preceding transient ischaemic attack, which is clinically defined as focal neurological symptoms of ischaemic origin resolving spontaneously. Failure to diagnose transient ischaemic attack is a wasted opportunity to prevent recurrent disabling stroke. Unfortunately, diagnosis can be difficult, due to numerous mimics, and to the absence of a specific test. New diagnostic tools are thus needed, in particular for radiologically silent cases, which correspond to the recommended tissue-based definition of transient ischaemic attack. As endothelial activation is a hallmark of cerebrovascular events, we postulated that this may also be true for transient ischaemic attack, and that it would be clinically relevant to develop non-invasive in vivo imaging to detect this endothelial activation. Using transcriptional and immunohistological analyses for adhesion molecules in a mouse model, we identified brain endothelial P-selectin as a potential biomarker for transient ischaemic attack. We thus developed ultra-sensitive molecular magnetic resonance imaging using antibody-based microparticles of iron oxide targeting P-selectin. This highly sensitive imaging strategy unmasked activated endothelial cells after experimental transient ischaemic attack and allowed discriminating transient ischaemic attack from epilepsy and migraine, two important transient ischaemic attack mimics. We provide preclinical evidence that combining conventional magnetic resonance imaging with molecular magnetic resonance imaging targeting P-selectin might aid in the diagnosis of transient ischaemic attack.
F376A/M388A-solulin, a new promising antifibrinolytic for severe haemophilia A.
Parcq J, Petersen KU, Borel-Derlon A, Gautier P, Ebel M, Vivien D, Repessé Y
Haemophilia 1365-2516
PMID : 27928886
KEYWORDS : Factor VIII|therapeutic use|Fibrinolysis|physiology|Hemophilia A|drug therapy|Humans
Show abstract [+]
Haemophilia is a major bleeding disorder due to a deficiency of procoagulant factor VIII (type A) or IX (type B). The treatment is substitutive and based on infusion of factor concentrates. Main limitations of this therapy are cost, short factor half-life and the development of inhibitors (up to 30% of severe HA patients). An important aggravating factor of haemophilia is due to a premature fibrinolysis, directing attention to the therapeutic potential of suitable antifibrinolytics. Thrombomodulin (TM) is a key player of the coagulation cascade by activating protein C (an inhibitor of thrombin generation, thus antagonizing coagulation) and of the fibrinolytic cascade by activating thrombin activatable fibrinolysis inhibitor TAFI (thus reducing fibrinolysis). Solulin is a soluble form of TM that shows both capabilities.
Distant Space Processing is Controlled by tPA-dependent NMDA Receptor Signaling in the Entorhinal Cortex.
Hébert M, Anfray A, Chevilley A, Martinez de Lizarrondo S, Quenault A, Louessard M, Roussel BD, Obiang P, Save E, Orset C, Maubert E, Vivien D, Agin V
Cereb Cortex 1460-2199
PMID : 27613436
KEYWORDS : Aging|Animals|Calcium|metabolism|Entorhinal Cortex|metabolism|Female|Hippocampus|metabolism|Male|Mice, Knockout|Neurons|metabolism|Receptors, N-Methyl-D-Aspartate|metabolism|Signal Transduction|physiology|Tissue Plasminogen Activator|deficiency
Show abstract [+]
In humans, spatial cognition and navigation impairments are a frequent situation during physiological and pathological aging, leading to a dramatic deterioration in the quality of life. Despite the discovery of neurons with location-specific activity in rodents, that is, place cells in the hippocampus and later on grid cells in the entorhinal cortex (EC), the molecular mechanisms underlying spatial cognition are still poorly known. Our present data bring together in an unusual combination 2 molecules of primary biological importance: a major neuronal excitatory receptor, N-methyl-D-aspartate receptor (NMDAR), and an extracellular protease, tissue plasminogen activator (tPA), in the control of spatial navigation. By using tPA-deficient mice and a structure-selective pharmacological approach, we demonstrate that the tPA-dependent NMDAR signaling potentiation in the EC plays a key and selective role in the encoding and the subsequent use of distant landmarks during spatial learning. We also demonstrate that this novel function of tPA in the EC is reduced during aging. Overall, these results argue for the concept that encoding of proximal versus distal landmarks is mediated not only by different anatomical pathways but also by different molecular mechanisms, with the tPA-dependent potentiation of NMDAR signaling in the EC that plays an important role.
2016
The "inflammatory penumbra" in ischemic stroke: From clinical data to experimental evidence.
Gauberti M, De Lizarrondo SM, Vivien D
Eur Stroke J 2396-9881
PMID : 31008264
Show abstract [+]
The objective of the present review is to provide an overview of the available clinical and preclinical data supporting the existence of an "inflammatory penumbra" in ischemic stroke.
[Role of endothelial NMDA receptors in a mouse model of multiple sclerosis].
Macrez R, Vivien D, Docagne F
Med Sci (Paris) 1958-5381
PMID : 28044968
KEYWORDS : Animals|Antibodies, Monoclonal|therapeutic use|Blood-Brain Barrier|metabolism|Disease Models, Animal|Endothelium, Vascular|metabolism|Humans|Mice|Multiple Sclerosis|drug therapy|Receptors, N-Methyl-D-Aspartate|antagonists & inhibitors|Remission Induction
Retinal safety of intravitreal rtPA in healthy rats and under excitotoxic conditions.
Daruich A, Parcq J, Delaunay K, Naud MC, Le Rouzic Q, Picard E, Crisanti P, Vivien D, Berdugo M, Behar-Cohen F
Mol Vis 1090-0535
PMID : 27881907
KEYWORDS : Animals|Apoptosis|drug effects|Electroretinography|Intravitreal Injections|Male|Neurotoxins|toxicity|Rats, Long-Evans|Recombinant Proteins|administration & dosage|Retina|Retinal Ganglion Cells|drug effects|Tissue Plasminogen Activator|administration & dosage
Show abstract [+]
Intravitreal recombinant tissue plasminogen activator (rtPA) is used off-label for the surgical management of submacular hemorrhage, a severe complication of neovascular age-related macular degeneration. rtPA is approved for coronary and cerebral thrombolysis. However, in ischemic stroke rtPA is known to increase excitotoxic neural cell death by interacting with the N-methyl-D-aspartate (NMDA) receptor. We therefore investigated the retinal toxicity of rtPA in healthy rats and in a model of NMDA-induced retinal excitotoxicity.
Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors.
Lesept F, Chevilley A, Jezequel J, Ladépêche L, Macrez R, Aimable M, Lenoir S, Bertrand T, Rubrecht L, Galea P, Lebouvier L, Petersen KU, Hommet Y, Maubert E, Ali C, Groc L, Vivien D
Cell Death Dis 2041-4889
PMID : 27831563
KEYWORDS : Animals|Antibodies, Monoclonal|pharmacology|Calcium|metabolism|Cell Death|drug effects|Cell Membrane|drug effects|Diffusion|Fibrinolysin|pharmacology|HEK293 Cells|Humans|Lysine|metabolism|Male|Mice, Inbred BALB C|Neurons|cytology|Neurotoxins|toxicity|Protein Domains|Rats, Sprague-Dawley|Receptors, N-Methyl-D-Aspartate|chemistry|Signal Transduction|drug effects|Synapses|drug effects|Tissue Plasminogen Activator|pharmacology
Show abstract [+]
N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling.
Proportion of single-chain recombinant tissue plasminogen activator and outcome after stroke.
Leys D, Hommet Y, Jacquet C, Moulin S, Sibon I, Mas JL, Moulin T, Giroud M, Sagnier S, Cordonnier C, Medeiros de Bustos E, Turc G, Ronzière T, Bejot Y, Detante O, Ouk T, Mendyk AM, Favrole P, Zuber M, Triquenot-Bagan A, Ozkul-Wermester O, Montoro FM, Lamy C, Faivre A, Lebouvier L, Potey C, Poli M, Hénon H, Renou P, Dequatre-Ponchelle N, Bodenant M, Debruxelles S, Rossi C, Bordet R, Vivien D,
Neurology 1526-632X
PMID : 27815401
KEYWORDS : Aged|Aged, 80 and over|Brain Ischemia|complications|Cerebral Hemorrhage|complications|Disability Evaluation|Female|Fibrinolytic Agents|chemistry|Humans|Male|Middle Aged|Recombinant Proteins|chemistry|Seizures|complications|Severity of Illness Index|Stroke|complications|Thrombolytic Therapy|Time-to-Treatment|Tissue Plasminogen Activator|chemistry|Treatment Outcome
Show abstract [+]
To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia.
Valproic acid: a relevant thromboprophylactic strategy?
Martinez de Lizarrondo S, Gauberti M, Vivien D
J Thromb Haemost 1538-7836
PMID : 27709777
KEYWORDS : Humans|Valproic Acid
Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities.
Macrez R, Stys PK, Vivien D, Lipton SA, Docagne F
Lancet Neurol 1474-4465
PMID : 27571160
KEYWORDS : Biomarkers|metabolism|Excitatory Amino Acid Antagonists|therapeutic use|Glutamic Acid|metabolism|Humans|Multiple Sclerosis|drug therapy
Show abstract [+]
Research advances support the idea that excessive activation of the glutamatergic pathway plays an important part in the pathophysiology of multiple sclerosis. Beyond the well established direct toxic effects on neurons, additional sites of glutamate-induced cell damage have been described, including effects in oligodendrocytes, astrocytes, endothelial cells, and immune cells. Such toxic effects could provide a link between various pathological aspects of multiple sclerosis, such as axonal damage, oligodendrocyte cell death, demyelination, autoimmunity, and blood-brain barrier dysfunction. Understanding of the mechanisms underlying glutamate toxicity in multiple sclerosis could help in the development of new approaches for diagnosis, treatment, and follow-up in patients with this debilitating disease. While several clinical trials of glutamatergic modulators have had disappointing results, our growing understanding suggests that there is reason to remain optimistic about the therapeutic potential of these drugs.
Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism.
Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J, Vivien D, Gauberti M
Blood 1528-0020
PMID : 27531677
KEYWORDS : Animals|Blood-Brain Barrier|drug effects|Bradykinin|metabolism|Bradykinin B2 Receptor Antagonists|pharmacology|Brain|drug effects|Capillary Permeability|drug effects|Fibrinolysin|metabolism|Fibrinolysis|drug effects|Hydrodynamics|Mice|Mice, Transgenic|Receptor, Bradykinin B2|genetics|Signal Transduction|drug effects|Tissue Plasminogen Activator|genetics
Show abstract [+]
Hyperfibrinolysis is a systemic condition occurring in various clinical disorders such as trauma, liver cirrhosis, and leukemia. Apart from increased bleeding tendency, the pathophysiological consequences of hyperfibrinolysis remain largely unknown. Our aim was to develop an experimental model of hyperfibrinolysis and to study its effects on the homeostasis of the blood-brain barrier (BBB). We induced a sustained hyperfibrinolytic state in mice by hydrodynamic transfection of a plasmid encoding for tissue-type plasminogen activator (tPA). As revealed by near-infrared fluorescence imaging, hyperfibrinolytic mice presented a significant increase in BBB permeability. Using a set of deletion variants of tPA and pharmacological approaches, we demonstrated that this effect was independent of N-methyl-D-aspartate receptor, low-density lipoprotein-related protein, protease-activated receptor-1, or matrix metalloproteinases. In contrast, we provide evidence that hyperfibrinolysis-induced BBB leakage is dependent on plasmin-mediated generation of bradykinin and subsequent activation of bradykinin B2 receptors. Accordingly, this effect was prevented by icatibant, a clinically available B2 receptor antagonist. In agreement with these preclinical data, bradykinin generation was also observed in humans in a context of acute pharmacological hyperfibrinolysis. Altogether, these results suggest that B2 receptor blockade may be a promising strategy to prevent the deleterious effects of hyperfibrinolysis on the homeostasis of the BBB.
Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis.
Macrez R, Ortega MC, Bardou I, Mehra A, Fournier A, Van der Pol SM, Haelewyn B, Maubert E, Lesept F, Chevilley A, de Castro F, De Vries HE, Vivien D, Clemente D, Docagne F
Brain 1460-2156
PMID : 27435092
KEYWORDS : Animals|Blood-Brain Barrier|metabolism|Encephalomyelitis, Autoimmune, Experimental|drug therapy|Endothelial Cells|Excitatory Amino Acid Antagonists|pharmacology|HEK293 Cells|Humans|Male|Mice|Mice, Inbred C57BL|Mice, Knockout|Nerve Tissue Proteins|drug effects|Receptors, N-Methyl-D-Aspartate|drug effects|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.
Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis.
Orset C, Haelewyn B, Allan SM, Ansar S, Campos F, Cho TH, Durand A, El Amki M, Fatar M, Garcia-Yébenes I, Gauberti M, Grudzenski S, Lizasoain I, Lo E, Macrez R, Margaill I, Maysami S, Meairs S, Nighoghossian N, Orbe J, Paramo JA, Parienti JJ, Rothwell NJ, Rubio M, Waeber C, Young AR, Touzé E, Vivien D
Stroke 1524-4628
PMID : 27032444
KEYWORDS : Animals|Brain Ischemia|drug therapy|Disease Models, Animal|Fibrinolytic Agents|administration & dosage|Infarction, Middle Cerebral Artery|drug therapy|Male|Mice|Mice, Inbred C57BL|Stroke|drug therapy|Tissue Plasminogen Activator|administration & dosage
Show abstract [+]
The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator.
Nano-zymography Using Laser-Scanning Confocal Microscopy Unmasks Proteolytic Activity of Cell-Derived Microparticles.
Briens A, Gauberti M, Parcq J, Montaner J, Vivien D, Martinez de Lizarrondo S
Theranostics 1838-7640
PMID : 27022410
KEYWORDS : Animals|Cell-Derived Microparticles|chemistry|Disease Models, Animal|Humans|Mice|Microscopy, Confocal|methods|Peptide Hydrolases|analysis|Plasma|chemistry|Stroke|pathology
Show abstract [+]
Cell-derived microparticles (MPs) are nano-sized vesicles released by activated cells in the extracellular milieu. They act as vectors of biological activity by carrying membrane-anchored and cytoplasmic constituents of the parental cells. Although detection and characterization of cell-derived MPs may be of high diagnostic and prognostic values in a number of human diseases, reliable measurement of their size, number and biological activity still remains challenging using currently available methods. In the present study, we developed a protocol to directly image and functionally characterize MPs using high-resolution laser-scanning confocal microscopy. Once trapped on annexin-V coated micro-wells, we developed several assays using fluorescent reporters to measure their size, detect membrane antigens and evaluate proteolytic activity (nano-zymography). In particular, we demonstrated the applicability and specificity of this method to detect antigens and proteolytic activities of tissue-type plasminogen activator (tPA), urokinase and plasmin at the surface of engineered MPs from transfected cell-lines. Furthermore, we were able to identify a subset of tPA-bearing fibrinolytic MPs using plasma samples from a cohort of ischemic stroke patients who received thrombolytic therapy and in an experimental model of thrombin-induced ischemic stroke in mice. Overall, this method is promising for functional characterization of cell-derived MPs.
Artificial antigen-presenting cells expressing HLA class II molecules as an effective tool for amplifying human specific memory CD4(+) T cells.
Garnier A, Hamieh M, Drouet A, Leprince J, Vivien D, Frébourg T, Le Mauff B, Latouche JB, Toutirais O
Immunol Cell Biol 1440-1711
PMID : 26924643
KEYWORDS : Animals|Antigen Presentation|immunology|Antigen-Presenting Cells|immunology|Artificial Cells|immunology|CD4-Positive T-Lymphocytes|cytology|Cell Proliferation|Epitopes|immunology|Histocompatibility Antigens Class II|metabolism|Humans|Immunologic Memory|Lymphocyte Activation|immunology|Mice|NIH 3T3 Cells|Peptides|metabolism|Phenotype|Tissue Donors
Show abstract [+]
Owing to their multiple immune functions, CD4(+) T cells are of major interest for immunotherapy in chronic viral infections and cancer, as well as for severe autoimmune diseases and transplantation. Therefore, standardized methods allowing rapid generation of a large number of CD4(+) T cells for adoptive immunotherapy are still awaited. We constructed stable artificial antigen-presenting cells (AAPCs) derived from mouse fibroblasts. They were genetically modified to express human leukocyte antigen (HLA)-DR molecules and the human accessory molecules B7.1, Intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-3 (LFA-3). AAPCs expressing HLA-DR1, HLA-DR15 or HLA-DR51 molecules and loaded with peptides derived from influenza hemagglutinin (HA), myelin basic protein (MBP) or factor VIII, respectively, activated specific CD4(+) T-cell clones more effectively than Epstein-Barr virus (EBV)-transformed B cells. We also showed that AAPCs were able to take up and process whole Ag proteins, and present epitopes to specific T cells. In primary cultures, AAPCs loaded with HA peptide allowed generation of specific Th1 lymphocytes from healthy donors as demonstrated by tetramer and intracellular cytokine staining. Although AAPCs were less effective than autologous peripheral blood mononuclear cells (PBMCs) to stimulate CD4(+) T cells in primary culture, AAPCs were more potent to reactivate and expand memory Th1 cells in a strictly Ag-dependent manner. As the availability of autologous APCs is limited, the AAPC system represents a stable and reliable tool to achieve clinically relevant numbers of CD4(+) T cells for adoptive immunotherapy. For fundamental research in immunology, AAPCs are also useful to decipher mechanisms involved in the development of human CD4 T-cell responses.
Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations.
Mollereau B, Rzechorzek NM, Roussel BD, Sedru M, Van den Brink DM, Bailly-Maitre B, Palladino F, Medinas DB, Domingos PM, Hunot S, Chandran S, Birman S, Baron T, Vivien D, Duarte CB, Ryoo HD, Steller H, Urano F, Chevet E, Kroemer G, Ciechanover A, Calabrese EJ, Kaufman RJ, Hetz C
Brain Res 1872-6240
PMID : 26923166
KEYWORDS : Animals|Autophagy|Endoplasmic Reticulum Stress|physiology|Humans|Nervous System Diseases|complications|Proteasome Endopeptidase Complex|metabolism|Proteostasis Deficiencies|complications|Signal Transduction|Ubiquitin|metabolism|Unfolded Protein Response|physiology
Show abstract [+]
In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.
A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke.
Maysami S, Wong R, Pradillo JM, Denes A, Dhungana H, Malm T, Koistinaho J, Orset C, Rahman M, Rubio M, Schwaninger M, Vivien D, Bath PM, Rothwell NJ, Allan SM
J Cereb Blood Flow Metab 1559-7016
PMID : 26661169
KEYWORDS : Animals|Brain|drug effects|Brain Edema|complications|Brain Ischemia|complications|Disease Models, Animal|Drug Evaluation, Preclinical|Inflammation|complications|Interleukin 1 Receptor Antagonist Protein|therapeutic use|Male|Mice, Inbred BALB C|Mice, Inbred C57BL|Neuroprotective Agents|therapeutic use|Receptors, Interleukin-1|antagonists & inhibitors|Stroke|complications
Show abstract [+]
Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials.
The story of an exceptional serine protease, tissue-type plasminogen activator (tPA).
Hébert M, Lesept F, Vivien D, Macrez R
Rev Neurol (Paris) 0035-3787
PMID : 26626577
KEYWORDS : Animals|Brain Chemistry|genetics|Humans|Serine Proteases|genetics|Tissue Plasminogen Activator|genetics
Show abstract [+]
The only acute treatment of ischemic stroke approved by the health authorities is tissue recombinant plasminogen activator (tPA)-induced thrombolysis. Under physiological conditions, tPA, belonging to the serine protease family, is secreted by endothelial and brain cells (neurons, astrocytes, microglia, oligodendrocytes). Although revascularisation induced by tPA is beneficial during a stroke, research over the past 20 years shows that tPA can also be deleterious for the brain parenchyma. Thus, in this review of the literature, after a brief history on the discovery of tPA, we reviewed current knowledge of mechanisms by which tPA can influence brain function in physiological and pathological conditions.
The plasminogen activation system in neuroinflammation.
Mehra A, Ali C, Parcq J, Vivien D, Docagne F
Biochim Biophys Acta 0006-3002
PMID : 26493446
KEYWORDS : Animals|Blood-Brain Barrier|immunology|Central Nervous System Diseases|immunology|Fibrin|immunology|Fibrinolysin|immunology|Humans|Inflammation|immunology|Leukocytes|immunology|Microglia|immunology|Plasminogen|immunology|Tissue Plasminogen Activator|immunology
Show abstract [+]
The plasminogen activation (PA) system consists in a group of proteases and protease inhibitors regulating the activation of the zymogen plasminogen into its proteolytically active form, plasmin. Here, we give an update of the current knowledge about the role of the PA system on different aspects of neuroinflammation. These include modification in blood-brain barrier integrity, leukocyte diapedesis, removal of fibrin deposits in nervous tissues, microglial activation and neutrophil functions. Furthermore, we focus on the molecular mechanisms (some of them independent of plasmin generation and even of proteolysis) and target receptors responsible for these effects. The description of these mechanisms of action may help designing new therapeutic strategies targeting the expression, activity and molecular mediators of the PA system in neurological disorders involving neuroinflammatory processes. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.
Epidural Cortical Stimulation as a Treatment for Poststroke Aphasia: A Systematic Review of the Literature and Underlying Neurophysiological Mechanisms.
Balossier A, Etard O, Descat C, Vivien D, Emery E
Neurorehabil Neural Repair 1552-6844
PMID : 26422832
KEYWORDS : Aphasia, Broca|etiology|Cerebral Cortex|physiopathology|Electric Stimulation Therapy|methods|Humans|Stroke|complications
Show abstract [+]
Nearly 15 million people suffer from stroke every year worldwide, with about 20% of the survivors retaining chronic aphasic symptoms. Spontaneous recovery is limited to 3 to 6 months. Cortical stimulation techniques have been proposed to enhance the recovery process.
Tissue Plasminogen Activator Expression Is Restricted to Subsets of Excitatory Pyramidal Glutamatergic Neurons.
Louessard M, Lacroix A, Martineau M, Mondielli G, Montagne A, Lesept F, Lambolez B, Cauli B, Mothet JP, Vivien D, Maubert E
Mol Neurobiol 1559-1182
PMID : 26377106
KEYWORDS : Animals|Cells, Cultured|Excitatory Postsynaptic Potentials|physiology|Gene Expression|Glutamic Acid|metabolism|Male|Mice|Mice, Inbred C57BL|Mice, Knockout|Organ Culture Techniques|Pyramidal Cells|metabolism|Rats|Rats, Wistar|Synaptic Vesicles|metabolism|Tissue Plasminogen Activator|biosynthesis
Show abstract [+]
Although the extracellular serine protease tissue plasminogen activator (tPA) is involved in pathophysiological processes such as learning and memory, anxiety, epilepsy, stroke, and Alzheimer's disease, information about its regional, cellular, and subcellular distribution in vivo is lacking. In the present study, we observed, in healthy mice and rats, the presence of tPA in endothelial cells, oligodendrocytes, mastocytes, and ependymocytes, but not in pericytes, microglial cells, and astrocytes. Moreover, blockage of the axo-dendritic transport unmasked tPA expression in neurons of cortical and hippocampal areas. Interestingly, combined electrophysiological recordings, single-cell reverse transcription polymerase chain reaction (RT-PCR), and immunohistological analyses revealed that the presence of tPA is restricted to subsets of excitatory pyramidal glutamatergic neurons. We further evidenced that tPA is stored in synaptobrevin-2-positive glutamatergic synaptic vesicles. Based on all these data, we propose the existence of tPA-ergic neurons in the mature brain.
Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism.
Lemarchand E, Maubert E, Haelewyn B, Ali C, Rubio M, Vivien D
Cell Death Differ 1476-5403
PMID : 26068590
KEYWORDS : Animals|Brain Ischemia|genetics|Cell Death|genetics|Central Nervous System|metabolism|ErbB Receptors|genetics|Glucose|metabolism|Hippocampus|metabolism|Mice|Neurons|metabolism|Oxygen|metabolism|Rats|Signal Transduction|Tissue Plasminogen Activator|genetics
Show abstract [+]
In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mice were more sensitive to OGD than wild-type slices. Pharmacological approaches targeting the known receptors of tPA revealed that only the inhibition of phosphorylation of epidermal growth factor receptors (EGFRs) prevented the neuroprotective effect of endogenous tPA. This study shows that ischemic hippocampal neurons overproduce endogenous tPA as an intend to protect themselves from ischemic death, by a mechanism involving an activation of EGFRs. Thus, strategies contributing to promote either endogenous production of tPA or its associated EGFR-linked signaling pathway may have beneficial effects following brain injuries such as stroke.
Normalization of Reverse Transcription Quantitative PCR Data During Ageing in Distinct Cerebral Structures.
Bruckert G, Vivien D, Docagne F, Roussel BD
Mol Neurobiol 1559-1182
PMID : 25663136
KEYWORDS : Aging|genetics|Algorithms|Animals|Brain Chemistry|genetics|Cerebellum|metabolism|Cerebral Cortex|growth & development|Corpus Striatum|growth & development|Gene Expression Profiling|Hippocampus|metabolism|Male|Mice|Mice, Inbred C57BL|Nerve Tissue Proteins|biosynthesis|Reverse Transcriptase Polymerase Chain Reaction
Show abstract [+]
Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) has become a routine method in many laboratories. Normalization of data from experimental conditions is critical for data processing and is usually achieved by the use of a single reference gene. Nevertheless, as pointed by the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines, several reference genes should be used for reliable normalization. Ageing is a physiological process that results in a decline of many expressed genes. Reliable normalization of RT-qPCR data becomes crucial when studying ageing. Here, we propose a RT-qPCR study from four mouse brain regions (cortex, hippocampus, striatum and cerebellum) at different ages (from 8 weeks to 22 months) in which we studied the expression of nine commonly used reference genes. With the use of two different algorithms, we found that all brain structures need at least two genes for a good normalization step. We propose specific pairs of gene for efficient data normalization in the four brain regions studied. These results underline the importance of reliable reference genes for specific brain regions in ageing.
2015
Impacts of tissue-type plasminogen activator (tPA) on neuronal survival.
Chevilley A, Lesept F, Lenoir S, Ali C, Parcq J, Vivien D
Front Cell Neurosci 1662-5102
PMID : 26528141
Show abstract [+]
Tissue-type plasminogen activator (tPA) a serine protease is constituted of five functional domains through which it interacts with different substrates, binding proteins, and receptors. In the last years, great interest has been given to the clinical relevance of targeting tPA in different diseases of the central nervous system, in particular stroke. Among its reported functions in the central nervous system, tPA displays both neurotrophic and neurotoxic effects. How can the protease mediate such opposite functions remain unclear but several hypotheses have been proposed. These include an influence of the degree of maturity and/or the type of neurons, of the level of tPA, of its origin (endogenous or exogenous) or of its form (single chain tPA versus two chain tPA). In this review, we will provide a synthetic snapshot of our current knowledge regarding the natural history of tPA and discuss how it sustains its pleiotropic functions with focus on excitotoxic/ischemic neuronal death and neuronal survival.
Conformations of tissue plasminogen activator (tPA) orchestrate neuronal survival by a crosstalk between EGFR and NMDAR.
Bertrand T, Lesept F, Chevilley A, Lenoir S, Aimable M, Briens A, Hommet Y, Bardou I, Parcq J, Vivien D
Cell Death Dis 2041-4889
PMID : 26469972
KEYWORDS : Apoptosis|Calcium Signaling|Cell Survival|ErbB Receptors|metabolism|Female|Humans|Protein Conformation|Receptor Cross-Talk|Receptors, N-Methyl-D-Aspartate|metabolism|Tissue Plasminogen Activator|chemistry
Show abstract [+]
Tissue-type plasminogen activator (tPA) is a pleiotropic serine protease of the central nervous system (CNS) with reported neurotrophic and neurotoxic functions. Produced and released under its single chain form (sc), the sc-tPA can be cleaved by plasmin or kallikrein in a two chain form, tc-tPA. Although both sc-tPA and tc-tPA display a similar fibrinolytic activity, we postulated here that these two conformations of tPA (sc-tPA and tc-tPA) could differentially control the effects of tPA on neuronal survival. Using primary cultures of mouse cortical neurons, our present study reveals that sc-tPA is the only one capable to promote N-methyl-D-aspartate receptor (NMDAR)-induced calcium influx and subsequent excitotoxicity. In contrast, both sc-tPA and tc-tPA are capable to activate epidermal growth factor receptors (EGFRs), a mechanism mediating the antiapoptotic effects of tPA. Interestingly, we revealed a tPA dependent crosstalk between EGFR and NMDAR in which a tPA-dependent activation of EGFRs leads to downregulation of NMDAR signaling and to subsequent neurotrophic effects.
Unmasking Silent Endothelial Activation in the Cardiovascular System Using Molecular Magnetic Resonance Imaging.
Belliere J, Martinez de Lizarrondo S, Choudhury RP, Quenault A, Le Béhot A, Delage C, Chauveau D, Schanstra JP, Bascands JL, Vivien D, Gauberti M
Theranostics 1838-7640
PMID : 26379785
KEYWORDS : Animals|Cardiovascular Diseases|diagnosis|Cardiovascular System|pathology|Disease Models, Animal|Endothelium, Vascular|pathology|Magnetic Resonance Imaging|methods|Mice|Molecular Imaging|methods
Show abstract [+]
Endothelial activation is a hallmark of cardiovascular diseases, acting either as a cause or a consequence of organ injury. To date, we lack suitable methods to measure endothelial activation in vivo. In the present study, we developed a magnetic resonance imaging (MRI) method allowing non-invasive endothelial activation mapping in the vasculature of the main organs affected during cardiovascular diseases. In clinically relevant contexts in mice (including systemic inflammation, acute and chronic kidney diseases, diabetes mellitus and normal aging), we provided evidence that this method allows detecting endothelial activation before any clinical manifestation of organ failure in the brain, kidney and heart with an exceptional sensitivity. In particular, we demonstrated that diabetes mellitus induces chronic endothelial cells activation in the kidney and heart. Moreover, aged mice presented activated endothelial cells in the kidneys and the cerebrovasculature. Interestingly, depending on the underlying condition, the temporospatial patterns of endothelial activation in the vascular beds of the cardiovascular system were different. These results demonstrate the feasibility of detecting silent endothelial activation occurring in conditions associated with high cardiovascular risk using molecular MRI.
Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia.
Llovera G, Hofmann K, Roth S, Salas-Pérdomo A, Ferrer-Ferrer M, Perego C, Zanier ER, Mamrak U, Rex A, Party H, Agin V, Fauchon C, Orset C, Haelewyn B, De Simoni MG, Dirnagl U, Grittner U, Planas AM, Plesnila N, Vivien D, Liesz A
Sci Transl Med 1946-6242
PMID : 26246166
KEYWORDS : Acute Disease|Animals|Antibodies, Monoclonal|therapeutic use|Brain Ischemia|drug therapy|Disease Models, Animal|Drug Evaluation, Preclinical|Humans|Integrin alpha4|immunology|Mice|Random Allocation|Treatment Outcome
Show abstract [+]
Numerous treatments have been reported to provide a beneficial outcome in experimental animal stroke models; however, these treatments (with the exception of tissue plasminogen activator) have failed in clinical trials. To improve the translation of treatment efficacy from bench to bedside, we have performed a preclinical randomized controlled multicenter trial (pRCT) to test a potential stroke therapy under circumstances closer to the design and rigor of a clinical randomized control trial. Anti-CD49d antibodies, which inhibit the migration of leukocytes into the brain, were previously investigated in experimental stroke models by individual laboratories. Despite the conflicting results from four positive and one inconclusive preclinical studies, a clinical trial was initiated. To confirm the preclinical results and to test the feasibility of conducting a pRCT, six independent European research centers investigated the efficacy of anti-CD49d antibodies in two distinct mouse models of stroke in a centrally coordinated, randomized, and blinded approach. The results pooled from all research centers revealed that treatment with CD49d-specific antibodies significantly reduced both leukocyte invasion and infarct volume after the permanent distal occlusion of the middle cerebral artery, which causes a small cortical infarction. In contrast, anti-CD49d treatment did not reduce lesion size or affect leukocyte invasion after transient proximal occlusion of the middle cerebral artery, which induces large lesions. These results suggest that the benefits of immune-targeted approaches may depend on infarct severity and localization. This study supports the feasibility of performing pRCTs.
Letter by Macrez et al. Regarding Article, "Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke".
Macrez R, Vivien D, Docagne F
Stroke 1524-4628
PMID : 26022638
KEYWORDS : Autoantibodies|analysis|Brain Ischemia|pathology|Female|Humans|Male|Receptors, N-Methyl-D-Aspartate|immunology|Stroke|pathology
Impact of alcohol consumption on the outcome of ischemic stroke and thrombolysis: role of the hepatic clearance of tissue-type plasminogen activator.
Lemarchand E, Gauberti M, Martinez de Lizarrondo S, Villain H, Repessé Y, Montagne A, Vivien D, Ali C, Rubio M
Stroke 1524-4628
PMID : 25922513
KEYWORDS : Alcohol Drinking|adverse effects|Animals|Brain Ischemia|drug therapy|Disease Models, Animal|Liver|metabolism|Low Density Lipoprotein Receptor-Related Protein-1|metabolism|Mice|Stroke|drug therapy|Thrombolytic Therapy|Tissue Plasminogen Activator|pharmacokinetics
Show abstract [+]
Tissue-type plasminogen activator (tPA) is the only acute treatment for ischemic stroke. Unfortunately, the benefit of tPA-driven thrombolysis is not systematic, and understanding the reasons for this is mandatory. The balance between beneficial and detrimental effects of tPA might explain the limited overall efficiency of thrombolysis. Here, we investigated whether this balance could be influenced by excessive alcohol intake.
Letter by Gauberti and Vivien regarding article, "amplification of regulatory T cells using a CD28 superagonist reduces brain damage after ischemic stroke in mice".
Gauberti M, Vivien D
Stroke 1524-4628
PMID : 25586834
KEYWORDS : Animals|Brain|immunology|CD28 Antigens|agonists|Infarction, Middle Cerebral Artery|immunology|T-Lymphocytes, Regulatory|immunology
Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke.
Wyseure T, Rubio M, Denorme F, Martinez de Lizarrondo S, Peeters M, Gils A, De Meyer SF, Vivien D, Declerck PJ
Blood 1528-0020
PMID : 25540192
KEYWORDS : Animals|Antibodies, Bispecific|chemistry|Disease Models, Animal|Female|Fibrinolytic Agents|therapeutic use|Histone Acetyltransferases|immunology|Immunotherapy|Male|Mice|Mice, Inbred C57BL|Protein Multimerization|Serpin E2|immunology|Stroke|pathology|TATA-Binding Protein Associated Factors|immunology|Therapies, Investigational|methods|Transcription Factor TFIID|immunology|Venous Thromboembolism|pathology
Show abstract [+]
Circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are causal factors for thrombolytic failure. Therefore, we evaluated an antibody-engineered bispecific inhibitor against TAFI and PAI-1 (heterodimer diabody, Db-TCK26D6x33H1F7) in several mouse models of thrombosis and stroke. Prophylactic administration of the diabody (0.8 mg/kg) in a thromboplastin-induced model of thromboembolism led to decreased lung fibrin deposition. In a model of cerebral ischemia and reperfusion, diabody administration (0.8 mg/kg, 1 hour postocclusion) led to a mitigated cerebral injury with a 2.3-fold reduced lesion and improved functional outcomes. In a mouse model of thrombin-induced middle cerebral artery occlusion, the efficacy of the diabody was compared to the standard thrombolytic treatment with recombinant tissue-type plasminogen activator (tPA). Early administration of diabody (0.8 mg/kg) caused a twofold decrease in brain lesion size, whereas that of tPA (10 mg/kg) had a much smaller effect. Delayed administration of diabody or tPA had no effect on lesion size, whereas the combined administration of diabody with tPA caused a 1.7-fold decrease in lesion size. In contrast to tPA, the diabody did not increase accumulative bleeding. In conclusion, administration of a bispecific inhibitor against TAFI and PAI-1 results in a prominent profibrinolytic effect in mice without increased bleeding.
NURR1 involvement in recombinant tissue-type plasminogen activator treatment complications after ischemic stroke.
Merino-Zamorano C, Hernández-Guillamon M, Jullienne A, Le Béhot A, Bardou I, Parés M, Fernández-Cadenas I, Giralt D, Carrera C, Ribó M, Vivien D, Ali C, Rosell A, Montaner J
Stroke 1524-4628
PMID : 25503547
KEYWORDS : Aged|Aged, 80 and over|Animals|Biomarkers|blood|Brain Ischemia|blood|Cell Line|Female|Fibrinolytic Agents|adverse effects|Humans|Inflammation|blood|Male|Mice|Middle Aged|Nuclear Receptor Subfamily 4, Group A, Member 2|biosynthesis|Stroke|blood|Tissue Plasminogen Activator|adverse effects|Treatment Outcome
Show abstract [+]
Despite the effectiveness of recombinant tissue-type plasminogen activator (r-tPA) during the acute phase of ischemic stroke, the therapy remains limited by a narrow time window and the occurrence of occasional vascular side effects, particularly symptomatic hemorrhages. Our aim was to investigate the mechanisms underlying the endothelial damage resulting from r-tPA treatment in ischemic-like conditions.
Understanding the functions of endogenous and exogenous tissue-type plasminogen activator during stroke.
Docagne F, Parcq J, Lijnen R, Ali C, Vivien D
Stroke 1524-4628
PMID : 25395410
KEYWORDS : Brain|physiology|Fibrinolytic Agents|therapeutic use|Humans|Stroke|drug therapy|Thrombolytic Therapy|Tissue Plasminogen Activator|physiology
BMP-2, hypoxia, and COL1A1/HtrA1 siRNAs favor neo-cartilage hyaline matrix formation in chondrocytes.
Ollitrault D, Legendre F, Drougard C, Briand M, Benateau H, Goux D, Chajra H, Poulain L, Hartmann D, Vivien D, Shridhar V, Baldi A, Mallein-Gerin F, Boumediene K, Demoor M, Galera P
Tissue Eng Part C Methods 1937-3392
PMID : 24957638
KEYWORDS : Aged|Aged, 80 and over|Animals|Bone Morphogenetic Protein 2|pharmacology|Cartilage, Articular|cytology|Cattle|Cell Hypoxia|drug effects|Cells, Cultured|Chondrocytes|Chondrogenesis|drug effects|Collagen Type I|metabolism|Collagen Type I, alpha 1 Chain|Extracellular Matrix|drug effects|High-Temperature Requirement A Serine Peptidase 1|Humans|Hyalin|metabolism|Hypertrophy|Kinetics|Mice, Nude|Middle Aged|Osteogenesis|drug effects|Phenotype|RNA, Messenger|genetics|RNA, Small Interfering|metabolism|Serine Endopeptidases|metabolism
Show abstract [+]
Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets.
2014
Molecular magnetic resonance imaging of brain-immune interactions.
Gauberti M, Montagne A, Quenault A, Vivien D
Front Cell Neurosci 1662-5102
PMID : 25505871
Show abstract [+]
Although the blood-brain barrier (BBB) was thought to protect the brain from the effects of the immune system, immune cells can nevertheless migrate from the blood to the brain, either as a cause or as a consequence of central nervous system (CNS) diseases, thus contributing to their evolution and outcome. Accordingly, as the interface between the CNS and the peripheral immune system, the BBB is critical during neuroinflammatory processes. In particular, endothelial cells are involved in the brain response to systemic or local inflammatory stimuli by regulating the cellular movement between the circulation and the brain parenchyma. While neuropathological conditions differ in etiology and in the way in which the inflammatory response is mounted and resolved, cellular mechanisms of neuroinflammation are probably similar. Accordingly, neuroinflammation is a hallmark and a decisive player of many CNS diseases. Thus, molecular magnetic resonance imaging (MRI) of inflammatory processes is a central theme of research in several neurological disorders focusing on a set of molecules expressed by endothelial cells, such as adhesion molecules (VCAM-1, ICAM-1, P-selectin, E-selectin, …), which emerge as therapeutic targets and biomarkers for neurological diseases. In this review, we will present the most recent advances in the field of preclinical molecular MRI. Moreover, we will discuss the possible translation of molecular MRI to the clinical setting with a particular emphasis on myeloperoxidase imaging, autologous cell tracking, and targeted iron oxide particles (USPIO, MPIO).
Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis?
Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, Touze E, Vivien D, Gauberti M
Stroke 1524-4628
PMID : 25190438
KEYWORDS : Animals|Cerebrospinal Fluid|physiology|Contrast Media|Disease Models, Animal|Image Interpretation, Computer-Assisted|Magnetic Resonance Imaging|methods|Mice|Stroke|cerebrospinal fluid|Subarachnoid Hemorrhage|cerebrospinal fluid
Show abstract [+]
The aim of the present study was to investigate the impact of different stroke subtypes on the glymphatic system using MRI.
Urokinase versus Alteplase for intraventricular hemorrhage fibrinolysis.
Gaberel T, Montagne A, Lesept F, Gauberti M, Lemarchand E, Orset C, Goulay R, Bertrand T, Emery E, Vivien D
Neuropharmacology 1873-7064
PMID : 24846802
KEYWORDS : Animals|Brain|drug effects|Brain Edema|drug therapy|Cells, Cultured|Cerebral Hemorrhage|drug therapy|Collagenases|Disease Models, Animal|Fibrinolysis|drug effects|Fibrinolytic Agents|pharmacology|Hematoma|drug therapy|Hydrocephalus|drug therapy|Male|Mice|Neuroimmunomodulation|drug effects|Random Allocation|Rats, Sprague-Dawley|Recovery of Function|drug effects|Tissue Plasminogen Activator|pharmacology|Urokinase-Type Plasminogen Activator|pharmacology
Show abstract [+]
Intraventricular hemorrhage (IVH) is the most severe form of stroke with intraventricular fibrinolysis (IVF) as a hopeful treatment. Urokinase (uPA) and tissue-type plasminogen activator (tPA) are used for IVF in Human. No clinical trial has evaluated the differential impact of these two fibrinolytics for IVF. Thus, we decided here to compare the use of these two fibrinolytics in a pre-clinical study. IVH was induced in rats by injection of collagenase type VII within the brain parenchyma followed by an IVF. Rats were randomized to receive uPA, tPA or saline within the ventricle, and cerebrospinal fluid was aspirated. Hematoma and ventricular volumes, brain water contents, inflammation and neurological deficits were measured at day three post-treatments. We also performed in vitro studies, in which neuronal cultures were subjected to an excitotoxic paradigm in the presence of either uPA or tPA. In the IVH model, we showed that although both uPA and tPA led to reduced ventricular volumes, only uPA significantly improved functional recovery. These results could be explained by the fact that uPA, in contrast of tPA, fails to promote inflammatory processes and neurotoxicity. Our study provides evidence supporting the use of uPA for fibrinolysis of IVH. A clinical trial could be warranted if tPA failed to improve outcomes in human IVH.
tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury.
Lemarchant S, Pruvost M, Hébert M, Gauberti M, Hommet Y, Briens A, Maubert E, Gueye Y, Féron F, Petite D, Mersel M, do Rego JC, Vaudry H, Koistinaho J, Ali C, Agin V, Emery E, Vivien D
Neurobiol Dis 1095-953X
PMID : 24576594
KEYWORDS : ADAM Proteins|metabolism|ADAMTS4 Protein|Animals|Axons|drug effects|Cells, Cultured|Chondroitin Sulfate Proteoglycans|metabolism|Female|Neurites|drug effects|Neurocan|Neuronal Plasticity|drug effects|Neuropeptides|pharmacology|Neuroprotective Agents|pharmacology|Plasminogen Activator Inhibitor 1|pharmacology|Procollagen N-Endopeptidase|metabolism|Rats|Rats, Wistar|Recovery of Function|Serine Proteinase Inhibitors|pharmacology|Serpins|pharmacology|Spinal Cord|drug effects|Spinal Cord Compression|drug therapy|Spinal Cord Injuries|drug therapy|Tissue Plasminogen Activator|antagonists & inhibitors|Neuroserpin
Show abstract [+]
Although tissue plasminogen activator (tPA) is known to promote neuronal remodeling in the CNS, no mechanism of how this plastic function takes place has been reported so far. We provide here in vitro and in vivo demonstrations that this serine protease neutralizes inhibitory chondroitin sulfate proteoglycans (CSPGs) by promoting their degradation via the direct activation of endogenous type 4 disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4). Accordingly, in a model of compression-induced spinal cord injury (SCI) in rats, we found that administration of either tPA or its downstream effector ADAMTS-4 restores the tPA-dependent activity lost after the SCI and thereby, reduces content of CSPGs in the spinal cord, a cascade of events leading to an improved axonal regeneration/sprouting and eventually long term functional recovery. This is the first study to reveal a tPA-ADAMTS-4 axis and its function in the CNS. It also raises the prospect of exploiting such cooperation as a therapeutic tool for enhancing recovery after acute CNS injuries.
GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice.
Le Behot A, Gauberti M, Martinez De Lizarrondo S, Montagne A, Lemarchand E, Repesse Y, Guillou S, Denis CV, Maubert E, Orset C, Vivien D
Blood 1528-0020
PMID : 24553181
KEYWORDS : Animals|Benzofurans|Blood Platelets|metabolism|Blood Vessels|metabolism|Hemorheology|Male|Mice|Platelet Aggregation|Platelet Glycoprotein GPIb-IX Complex|metabolism|Protein Interaction NotAllowedScript6629801e6b790Maps|Quinolines|Thrombosis|metabolism|von Willebrand Factor|metabolism
Show abstract [+]
Interactions between platelet glycoprotein (Gp) IIb/IIIa and plasma proteins mediate platelet cross-linking in arterial thrombi. However, GpIIb/IIIa inhibitors fail to disperse platelet aggregates after myocardial infarction or ischemic stroke. These results suggest that stability of occlusive thrombi involves additional and as-yet-unidentified mechanisms. In the present study, we investigated the mechanisms driving platelet cross-linking during occlusive thrombus formation. Using computational fluid dynamic simulations and in vivo thrombosis models, we demonstrated that the inner structure of occlusive thrombi is heterogeneous and primarily determined by the rheological conditions that prevailed during thrombus growth. Unlike the first steps of thrombus formation, which are GpIIb/IIIa-dependent, our findings reveal that closure of the arterial lumen is mediated by GpIbα-von Willebrand Factor (VWF) interactions. Accordingly, disruption of platelet cross-linking using GpIbα-VWF inhibitors restored vessel patency and improved outcome in a mouse model of ischemic stroke, although the thrombi were resistant to fibrinolysis or traditional antithrombotic agents. Overall, our study demonstrates that disruption of GpIbα-VWF interactions restores vessel patency after occlusive thrombosis by specifically disaggregating the external layer of occlusive thrombi, which is constituted of platelet aggregates formed under very high shear rates.
Lack of secondary microthrombosis after thrombin-induced stroke in mice and non-human primates.
Gauberti M, Martinez de Lizarrondo S, Orset C, Vivien D
J Thromb Haemost 1538-7836
PMID : 24354644
KEYWORDS : Animals|Blood Coagulation|Bradykinin|metabolism|Brain Diseases|prevention & control|Cerebrovascular Circulation|Factor XII|metabolism|Inflammation|Ischemia|pathology|Macaca mulatta|Male|Mice|Mice, Inbred C57BL|Stroke|chemically induced|T-Lymphocytes|cytology|Thrombin|adverse effects|Thrombosis|pathology|von Willebrand Factor|metabolism
Show abstract [+]
Secondary microthrombosis is a major pathophysiologic mechanism leading to brain damage following transient mechanical vascular occlusion (TMVO), the most widely used experimental stroke model. Whether secondary microthrombosis also occurs in non-TMVO stroke models represents an important issue for clinical translation of antimicrothrombosis therapeutic strategies.
2013
Intracerebral hematomas disappear on T2*-weighted images during normobaric oxygen therapy.
Gaberel T, Gakuba C, Hebert M, Montagne A, Agin V, Rubio M, Emery E, Vivien D, Gauberti M
Stroke 1524-4628
PMID : 24105700
KEYWORDS : Animals|Brain|pathology|Intracranial Hemorrhages|blood|Magnetic Resonance Imaging|Mice|Oxygen|blood|Oxygen Inhalation Therapy|Treatment Outcome
Show abstract [+]
The aim of the present study was to investigate the effects of normobaric oxygen (NBO) therapy on T2*-weighted images of intracranial hemorrhages (ICHs).
Ultra-sensitive molecular MRI of vascular cell adhesion molecule-1 reveals a dynamic inflammatory penumbra after strokes.
Gauberti M, Montagne A, Marcos-Contreras OA, Le Béhot A, Maubert E, Vivien D
Stroke 1524-4628
PMID : 23743972
KEYWORDS : Animals|Ferric Compounds|Image Enhancement|methods|Infarction, Middle Cerebral Artery|drug therapy|Inflammation|drug therapy|Intracranial Hemorrhages|chemically induced|Magnetic Resonance Imaging|instrumentation|Mice|Vascular Cell Adhesion Molecule-1|drug effects
Show abstract [+]
Our aim was to assess the spatiotemporal evolution of the cerebrovascular inflammation occurring after ischemic and hemorrhagic strokes using a recently developed, fast, and ultra-sensitive molecular MRI method.
Molecular requirements for safer generation of thrombolytics by bioengineering the tissue-type plasminogen activator A chain.
Parcq J, Bertrand T, Baron AF, Hommet Y, Anglès-Cano E, Vivien D
J Thromb Haemost 1538-7836
PMID : 23301636
KEYWORDS : Amino Acid Sequence|Animals|Bioengineering|instrumentation|Bioreactors|Cell Death|drug effects|Drug Design|Fibrinolysis|drug effects|Fibrinolytic Agents|metabolism|HEK293 Cells|Humans|Kringles|Mice|Molecular Sequence Data|Mutagenesis, Site-Directed|Neurons|drug effects|Neurotoxicity Syndromes|etiology|Point Mutation|Rats|Receptors, N-Methyl-D-Aspartate|drug effects|Recombinant Proteins|pharmacology|Structure-Activity Relationship|Thrombolytic Therapy|adverse effects|Tissue Plasminogen Activator|biosynthesis|Transfection
Show abstract [+]
Thrombolysis with tissue-type plasminogen activator (t-PA) is the only treatment approved for acute ischemic stroke. Although t-PA is an efficient clot lysis enzyme, it also causes damage to the neurovascular unit, including hemorrhagic transformations and neurotoxicity.
Immunotherapy blocking the tissue plasminogen activator-dependent activation of N-methyl-D-aspartate glutamate receptors improves hemorrhagic stroke outcome.
Gaberel T, Macrez R, Gauberti M, Montagne A, Hebert M, Petersen KU, Touze E, Agin V, Emery E, Ali C, Vivien D
Neuropharmacology 1873-7064
PMID : 23219658
KEYWORDS : Animals|Antibodies, Monoclonal, Murine-Derived|administration & dosage|Immunotherapy|methods|Intracranial Hemorrhages|immunology|Male|Mice|Random Allocation|Rats|Rats, Sprague-Dawley|Receptors, N-Methyl-D-Aspartate|metabolism|Stroke|immunology|Tissue Plasminogen Activator|antagonists & inhibitors|Treatment Outcome
Show abstract [+]
Ischemic and hemorrhagic strokes have different etiologies, but share some pathogenic mechanisms, including a pro-neurotoxic effect of endogenous tissue plasminogen activator (tPA) via N-methyl-d-Aspartate (NMDA) receptors. Thus, in a model of intracerebral hemorrhage in rats, we investigated the therapeutic value of a strategy of immunotherapy (αATD-GluN1 antibody) preventing the interaction of tPA with NMDA receptors. We found that a single intravenous injection of αATD-GluN1 reduced brain edema, neuronal death, microglial activation and functional deficits following intracerebral hemorrhage, without affecting the hematoma volume.
Epidural electrical stimulation for the treatment of chronic poststroke aphasia: still compulsory 6 years later!
Balossier A, Etard O, Descat C, Vivien D, Emery E
Br J Neurosurg 1360-046X
PMID : 22998751
KEYWORDS : Aphasia, Broca|etiology|Electric Stimulation Therapy|methods|Electrodes, Implanted|Female|Humans|Middle Aged|Stroke|complications
Show abstract [+]
Implanted cortical stimulation is foreseen to facilitate functional poststroke recovery. Until now, no study has concluded on its pathophysiological mechanism. We report a case of a 58-year-old patient for whom cortical stimulation triggered a drastic enhancement of speech performances. The effects remain reversible after 6 years of stimulation, reflecting intra/inter-hemispheric modulation.
2012
GluN2D subunit-containing NMDA receptors control tissue plasminogen activator-mediated spatial memory.
Obiang P, Macrez R, Jullienne A, Bertrand T, Lesept F, Ali C, Maubert E, Vivien D, Agin V
J Neurosci 1529-2401
PMID : 22972996
KEYWORDS : Animals|Glutamic Acid|metabolism|Male|Maze Learning|physiology|Memory, Short-Term|physiology|Mice|Mice, Knockout|Mice, Transgenic|Protein Subunits|Receptors, N-Methyl-D-Aspartate|metabolism|Space Perception|physiology|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Tissue plasminogen activator (tPA) is a serine protease with pleiotropic actions in the CNS, such as synaptic plasticity and neuronal death. Some effects of tPA require its interaction with the GluN1 subunit of the NMDA receptor (NMDAR), leading to a potentiation of NMDAR signaling. We have reported previously that the pro-neurotoxic effect of tPA is mediated through GluN2D subunit-containing NMDARs. Thus, the aim of the present study was to determine whether GluN2D subunit-containing NMDARs drive tPA-mediated cognitive functions. To address this issue, a strategy of immunization designed to prevent the in vivo interaction of tPA with NMDARs and GluN2D-deficient mice were used in a set of behavioral tasks. Altogether, our data provide the first evidence that tPA influences spatial memory through its preferential interaction with GluN2D subunit-containing NMDARs.
Memantine improves safety of thrombolysis for stroke.
Montagne A, Hébert M, Jullienne A, Lesept F, Le Béhot A, Louessard M, Gauberti M, Orset C, Ali C, Agin V, Maubert E, Vivien D
Stroke 1524-4628
PMID : 22879098
KEYWORDS : Animals|Cells, Cultured|Cerebral Cortex|drug effects|Chemotherapy, Adjuvant|Excitatory Amino Acid Antagonists|pharmacology|Fibrinolytic Agents|adverse effects|In Vitro Techniques|Magnetic Resonance Imaging|Male|Memantine|pharmacology|Mice|Models, Animal|N-Methylaspartate|pharmacology|Stroke|drug therapy|Thrombolytic Therapy|methods|Tissue Plasminogen Activator|adverse effects|Treatment Outcome
Show abstract [+]
Despite side effects including N-methyl-d-aspartate-mediated neurotoxicity, recombinant tissue-type plasminogen activator (rtPA) remains the only approved acute treatment for ischemic stroke. Memantine, used for treatment of Alzheimer disease, is an antagonist for N-methyl-d-aspartate receptors. We investigated whether memantine could be used as a neuroprotective adjunct therapy for rtPA-induced thrombolysis after stroke.
Ultra-sensitive molecular MRI of cerebrovascular cell activation enables early detection of chronic central nervous system disorders.
Montagne A, Gauberti M, Macrez R, Jullienne A, Briens A, Raynaud JS, Louin G, Buisson A, Haelewyn B, Docagne F, Defer G, Vivien D, Maubert E
Neuroimage 1095-9572
PMID : 22813950
KEYWORDS : Animals|Blotting, Western|Central Nervous System Diseases|diagnosis|Endothelial Cells|metabolism|Ferric Compounds|Immunohistochemistry|Magnetic Resonance Imaging|methods|Male|Metal Nanoparticles|Mice|Mice, Inbred C57BL|Molecular Imaging|methods|Real-Time Polymerase Chain Reaction|Reverse Transcriptase Polymerase Chain Reaction
Show abstract [+]
Since endothelial cells can be targeted by large contrast-carrying particles, molecular imaging of cerebrovascular cell activation is highly promising to evaluate the underlying inflammation of the central nervous system (CNS). In this study, we aimed to demonstrate that molecular magnetic resonance imaging (MRI) of cerebrovascular cell activation can reveal CNS disorders in the absence of visible lesions and symptoms. To this aim, we optimized contrast carrying particles targeting vascular cell adhesion molecule-1 and MRI protocols through both in vitro and in vivo experiments. Although, pre-contrast MRI images failed to reveal the ongoing pathology, contrast-enhanced MRI revealed hypoperfusion-triggered CNS injury in vascular dementia, unmasked amyloid-induced cerebrovascular activation in Alzheimer's disease and allowed monitoring of disease activity during experimental autoimmune encephalomyelitis. Moreover, contrast-enhanced MRI revealed the cerebrovascular cell activation associated with known risk factors of CNS disorders such as peripheral inflammation, ethanol consumption, hyperglycemia and aging. By providing a dramatically higher sensitivity than previously reported methods and molecular contrast agents, the technology described in the present study opens new avenues of investigation in the field of neuroinflammation.
Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity.
Parcq J, Bertrand T, Montagne A, Baron AF, Macrez R, Billard JM, Briens A, Hommet Y, Wu J, Yepes M, Lijnen HR, Dutar P, Anglés-Cano E, Vivien D
Cell Death Differ 1476-5403
PMID : 22743997
KEYWORDS : Animals|Calcium|metabolism|Cells, Cultured|Humans|Mice|Mitogen-Activated Protein Kinase 1|metabolism|Mitogen-Activated Protein Kinase 3|metabolism|N-Methylaspartate|toxicity|Neurons|drug effects|Receptors, N-Methyl-D-Aspartate|metabolism|Recombinant Proteins|genetics|Signal Transduction|drug effects|Tissue Plasminogen Activator|genetics
Show abstract [+]
Unlike other serine proteases that are zymogens, the single-chain form of tissue plasminogen activator (sc-tPA) exhibits an intrinsic activity similar to that of its cleaved two-chain form (tc-tPA), especially in the presence of fibrin. In the central nervous system tPA controls brain functions and dysfunctions through its proteolytic activity. We demonstrated here, both in vitro and in vivo, that the intrinsic activity of sc-tPA selectively modulates N-methyl-D-aspartate receptor (NMDAR) signaling as compared with tc-tPA. Thus, sc-tPA enhances NMDAR-mediated calcium influx, Erk(½) activation and neurotoxicity in cultured cortical neurons, excitotoxicity in the striatum and NMDAR-dependent long-term potentiation in the hippocampal CA-1 network. As the first demonstration of a differential function for sc-tPA and tc-tPA, this finding opens a new area of investigations on tPA functions in the absence of its allosteric regulator, fibrin.
Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals.
Cassé F, Bardou I, Danglot L, Briens A, Montagne A, Parcq J, Alahari A, Galli T, Vivien D, Docagne F
J Neurosci 1529-2401
PMID : 22496564
KEYWORDS : Albumins|metabolism|Animals|Astrocytes|drug effects|Cell Death|drug effects|Cells, Cultured|Clathrin|physiology|Dynamins|physiology|Endocytosis|drug effects|Flow Cytometry|Gene Silencing|Glutamic Acid|pharmacology|Immunohistochemistry|Low Density Lipoprotein Receptor-Related Protein-1|Mice|Neurons|drug effects|Plasmids|genetics|Protein Kinase C|metabolism|RNA|biosynthesis|Real-Time Polymerase Chain Reaction|Receptors, Kainic Acid|drug effects|Receptors, LDL|metabolism|Signal Transduction|drug effects|Synapsins|metabolism|Tissue Plasminogen Activator|metabolism|Transfection|Tumor Suppressor Proteins|metabolism|alpha-Macroglobulins|metabolism
Show abstract [+]
Tissue-type plasminogen activator (tPA) regulates physiological processes in the brain, such as learning and memory, and plays a critical role in neuronal survival and neuroinflammation in pathological conditions. Here we demonstrate, by combining mouse in vitro and in vivo data, that tPA is an important element of the cross talk between neurons and astrocytes. The data show that tPA released by neurons is constitutively endocytosed by astrocytes via the low-density lipoprotein-related protein receptor, and is then exocytosed in a regulated manner. The exocytotic recycling of tPA by astrocytes is inhibited in the presence of extracellular glutamate. Kainate receptors of astrocytes act as sensors of extracellular glutamate and, via a signaling pathway involving protein kinase C, modulate the exocytosis of tPA. Further, by thus capturing extracellular tPA, astrocytes serve to reduce NMDA-mediated responses potentiated by tPA. Overall, this work provides the first demonstration that the neuromodulator, tPA, may also be considered as a gliotransmitter.
Thrombotic stroke in the anesthetized monkey (Macaca mulatta): characterization by MRI--a pilot study.
Gauberti M, Obiang P, Guedin P, Balossier A, Gakuba C, Diependaele AS, Chazalviel L, Vivien D, Young AR, Agin V, Orset C
Cerebrovasc Dis 1421-9786
PMID : 22343114
KEYWORDS : Anesthesia|Anesthetics, Dissociative|Anesthetics, Inhalation|Animals|Atracurium|Craniotomy|Diffusion Magnetic Resonance Imaging|methods|Disease Models, Animal|Image Processing, Computer-Assisted|Infarction, Middle Cerebral Artery|complications|Ketamine|Macaca mulatta|Magnetic Resonance Angiography|methods|Magnetic Resonance Imaging|Male|Methyl Ethers|Neurologic Examination|Neuromuscular Nondepolarizing Agents|Nitrous Oxide|Pilot Projects|Reproducibility of Results|Sevoflurane|Stroke|etiology|Thromboembolism|complications
Show abstract [+]
The lack of a relevant stroke model in large nonhuman primates hinders the development of innovative diagnostic/therapeutic approaches concerned with this cerebrovascular disease. Our objective was to develop a novel and clinically relevant model of embolic stroke in the anesthetized monkey that incorporates readily available clinical imaging techniques and that would allow the possibility of drug delivery including strategies of reperfusion.
tPA in the injured central nervous system: different scenarios starring the same actor?
Lemarchant S, Docagne F, Emery E, Vivien D, Ali C, Rubio M
Neuropharmacology 1873-7064
PMID : 22079561
KEYWORDS : Brain Ischemia|metabolism|Central Nervous System|metabolism|Humans|Multiple Sclerosis|metabolism|Spinal Cord Injuries|metabolism|Stroke|metabolism|Tissue Plasminogen Activator|metabolism
Show abstract [+]
When in 1947, Astrup and Permin reported that animal tissues contain fibrinokinase, a plasminogen activator, and when Pennica and colleagues (Pennica et al., 1983) cloned and expressed human tissue plasminogen activator (tPA) in Escherichia coli in 1983, they might did not realize how much their pioneer work would impact the life of millions of patients suffering from myocardial infarction or ischemic stroke. Some years after, accumulating evidence shows that tPA is not just a plasminogen activator of endothelial origin. Indeed, the main function of tPA released from the endothelium is to convert fibrin-bound plasminogen into active plasmin, thus dissolving the fibrin meshwork of blood clots. But this serine protease is also expressed by several cell types, and its beneficial and deleterious actions stand beyond fibrinolysis or even proteolysis. We will review here the reported effects and mechanisms of action of tPA in the course of three different pathologies of the central nervous system (CNS): spinal cord injury, ischemic stroke and multiple sclerosis. While these three disorders have distinct aetiologies, they share some pathogenic mechanisms. We will depict the main "good" and "bad" sides of tPA described to date during each of these pathological situations, as well as the proposed mechanisms explaining these effects. We speculate that due to common pathogenic pathways, tPA's actions described in one particular disease could in fact occur in the others. Finally, we will evaluate if tPA could be a therapeutic target for these pathologies. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
Epidural electrical stimulation to improve chronic poststroke aphasia: a 5-year follow-up.
Balossier A, Etard O, Descat C, Vivien D, Emery E
Brain Stimul 1876-4754
PMID : 22037142
KEYWORDS : Aphasia|etiology|Electric Stimulation Therapy|methods|Epidural Space|Female|Follow-Up Studies|Humans|Middle Aged|Stroke|complications|Stroke Rehabilitation|Treatment Outcome
Show abstract [+]
Aphasia is an incapacitating deficit experienced by almost 25% of patients after a left hemispheric ischemic stroke. Spontaneous recovery is considered to be limited to a period of 3 to 6 months. Although speech therapy performed during the first weeks may speed up this process and enhance its outcome, beyond this period it fails to change the global prognosis.
2011
Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo.
Jullienne A, Montagne A, Orset C, Lesept F, Jane DE, Monaghan DT, Maubert E, Vivien D, Ali C
Mol Neurodegener 1750-1326
PMID : 21975018
Show abstract [+]
Tissue plasminogen activator (tPA) exerts multiple functions in the central nervous system, depending on the partner with which it interacts. In particular, tPA acts as a positive neuromodulator of N-methyl-D-aspartate glutamatergic receptors (NMDAR). At the molecular level, it has been proposed that the pro-neurotoxicity mediated by tPA might occur through extrasynaptic NMDAR containing the GluN2D subunit. Thus, selective antagonists targeting tPA/GluN2D-containing NMDAR signaling would be of interest to prevent noxious effects of tPA.
Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults.
Rubio M, Villain H, Docagne F, Roussel BD, Ramos JA, Vivien D, Fernandez-Ruiz J, Ali C
PLoS One 1932-6203
PMID : 21886913
KEYWORDS : Animals|Cannabinoids|agonists|Cell Death|drug effects|Cells, Cultured|Ethanol|pharmacology|Excitatory Amino Acid Agonists|pharmacology|Mice|N-Methylaspartate|analysis|Neurons|Neuroprotective Agents|Piperidines|pharmacology|Pyrazoles|pharmacology|Receptor, Cannabinoid, CB1|antagonists & inhibitors|Rimonabant|Substance Withdrawal Syndrome
Show abstract [+]
Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA)-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716) during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.
Impact of tissue plasminogen activator on the neurovascular unit: from clinical data to experimental evidence.
Vivien D, Gauberti M, Montagne A, Defer G, Touzé E
J Cereb Blood Flow Metab 1559-7016
PMID : 21878948
KEYWORDS : Acute Disease|Aging|pathology|Animals|Blood-Brain Barrier|drug effects|Brain|blood supply|Drug Administration Schedule|Fibrinolytic Agents|administration & dosage|Humans|Microvessels|drug effects|Stroke|drug therapy|Thrombolytic Therapy|methods|Tissue Plasminogen Activator|administration & dosage
Show abstract [+]
About 15 million strokes occur each year worldwide. As the number one cause of morbidity and acquired disability, stroke is a major drain on public health-care funding, due to long hospital stays followed by ongoing support in the community or nursing-home care. Although during the last 10 years we have witnessed a remarkable progress in the understanding of the pathophysiology of ischemic stroke, reperfusion induced by recombinant tissue-type plasminogen activator (tPA-Actilyse) remains the only approved acute treatment by the health authorities. The objective of the present review is to provide an overview of our present knowledge about the impact of tPA on the neurovascular unit during acute ischemic stroke.
Intraventricular fibrinolysis versus external ventricular drainage alone in intraventricular hemorrhage: a meta-analysis.
Gaberel T, Magheru C, Parienti JJ, Huttner HB, Vivien D, Emery E
Stroke 1524-4628
PMID : 21817146
KEYWORDS : Cerebral Hemorrhage|drug therapy|Cerebral Ventricles|surgery|Drainage|methods|Fibrinolytic Agents|therapeutic use|Humans|Injections, Intraventricular|Thrombolytic Therapy|methods|Tissue Plasminogen Activator|therapeutic use|Treatment Outcome
Show abstract [+]
The purpose of this study was to analyze the effect of intraventricular fibrinolysis (IVF) compared with external ventricular drainage alone on mortality and functional outcome in the management of intraventricular hemorrhage secondary to spontaneous supratentorial intracerebral hemorrhage.
Preclinical evidence toward the use of ketamine for recombinant tissue-type plasminogen activator-mediated thrombolysis under anesthesia or sedation.
Gakuba C, Gauberti M, Mazighi M, Defer G, Hanouz JL, Vivien D
Stroke 1524-4628
PMID : 21817137
KEYWORDS : Anesthetics, Dissociative|therapeutic use|Animals|Brain Ischemia|drug therapy|Fibrinolytic Agents|therapeutic use|Ketamine|therapeutic use|Magnetic Resonance Imaging|Male|Mice|Stroke|drug therapy|Thrombolytic Therapy|methods|Tissue Plasminogen Activator|therapeutic use|Treatment Outcome
Show abstract [+]
Endovascular treatment of ischemic stroke usually involves recombinant tissue-type plasminogen activator (rtPA)-mediated thrombolysis in anesthetized patients. Paradoxically, differential influences of anesthetic agents on thrombolysis outcome remain unknown.
Antibodies preventing the interaction of tissue-type plasminogen activator with N-methyl-D-aspartate receptors reduce stroke damages and extend the therapeutic window of thrombolysis.
Macrez R, Obiang P, Gauberti M, Roussel B, Baron A, Parcq J, Cassé F, Hommet Y, Orset C, Agin V, Bezin L, Berrocoso TG, Petersen KU, Montaner J, Maubert E, Vivien D, Ali C
Stroke 1524-4628
PMID : 21680906
KEYWORDS : Animals|Antibodies|immunology|Brain|drug effects|Brain Ischemia|drug therapy|Fibrinolytic Agents|immunology|Mice|Receptors, N-Methyl-D-Aspartate|immunology|Stroke|drug therapy|Tissue Plasminogen Activator|immunology
Show abstract [+]
Tissue-type plasminogen activator (tPA) is the only drug approved for the acute treatment of ischemic stroke but with two faces in the disease: beneficial fibrinolysis in the vasculature and damaging effects on the neurovascular unit and brain parenchyma. To improve this profile, we developed a novel strategy, relying on antibodies targeting the proneurotoxic effects of tPA.
HMGB-1 promotes fibrinolysis and reduces neurotoxicity mediated by tissue plasminogen activator.
Roussel BD, Mysiorek C, Rouhiainen A, Jullienne A, Parcq J, Hommet Y, Culot M, Berezowski V, Cecchelli R, Rauvala H, Vivien D, Ali C
J Cell Sci 1477-9137
PMID : 21610098
KEYWORDS : Animals|Biomarkers|blood|Blood-Brain Barrier|cytology|Calcium|metabolism|Cattle|Cells, Cultured|Coculture Techniques|Fibrinolysis|drug effects|HMG-Box Domains|HMGB1 Protein|metabolism|Humans|Mice|N-Methylaspartate|pharmacology|Neurons|drug effects|Neuroprotective Agents|pharmacology|Rats|Rats, Sprague-Dawley|Recombinant Proteins|pharmacology|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Owing to its ability to generate the clot-dissolving protease plasmin, tissue plasminogen activator (tPA) is the only approved drug for the acute treatment of ischemic stroke. However, tPA also promotes hemorrhagic transformation and excitotoxic events. High mobility group box-1 protein (HMGB-1) is a non-histone transcription factor and a pro-inflammatory cytokine, which has also been shown to bind to both tPA and plasminogen. We thus investigated the cellular and molecular effects through which HMGB-1 could influence the vascular and parenchymal effects of tPA during ischemia. We demonstrate that HMGB-1 not only increases clot lysis by tPA, but also reduces the passage of vascular tPA across the blood-brain barrier, as well as tPA-driven leakage of the blood-brain barrier. In addition, HMGB-1 prevents the pro-neurotoxic effect of tPA, by blocking its interaction with N-methyl-D-aspartate (NMDA) receptors and the attendant potentiation of NMDA-induced neuronal Ca²⁺ influx. In conclusion, we show in vitro that HMGB-1 can promote the beneficial effects of tPA while counteracting its deleterious properties. We suggest that derivatives of HMGB-1, devoid of pro-inflammatory properties, could be used as adjunctive therapies to improve the overall benefit of tPA-mediated thrombolysis following stroke.
Tissue plasminogen activator prevents white matter damage following stroke.
Correa F, Gauberti M, Parcq J, Macrez R, Hommet Y, Obiang P, Hernangómez M, Montagne A, Liot G, Guaza C, Maubert E, Ali C, Vivien D, Docagne F
J Exp Med 1540-9538
PMID : 21576385
KEYWORDS : Aging|Animals|Apoptosis|Brain|pathology|Brain Injuries|pathology|Caspase 3|metabolism|Cell Lineage|Cytokines|metabolism|Endothelium, Vascular|cytology|Epidermal Growth Factor|chemistry|Extracellular Signal-Regulated MAP Kinases|metabolism|Humans|Mice|Mice, Inbred C57BL|Oligodendroglia|cytology|Stroke|pathology|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Tissue plasminogen activator (tPA) is the only available treatment for acute stroke. In addition to its vascular fibrinolytic action, tPA exerts various effects within the brain, ranging from synaptic plasticity to control of cell fate. To date, the influence of tPA in the ischemic brain has only been investigated on neuronal, microglial, and endothelial fate. We addressed the mechanism of action of tPA on oligodendrocyte (OL) survival and on the extent of white matter lesions in stroke. We also investigated the impact of aging on these processes. We observed that, in parallel to reduced levels of tPA in OLs, white matter gets more susceptible to ischemia in old mice. Interestingly, tPA protects murine and human OLs from apoptosis through an unexpected cytokine-like effect by the virtue of its epidermal growth factor-like domain. When injected into aged animals, tPA, although toxic to the gray matter, rescues white matter from ischemia independently of its proteolytic activity. These studies reveal a novel mechanism of action of tPA and unveil OL as a target cell for cytokine effects of tPA in brain diseases. They show overall that tPA protects white matter from stroke-induced lesions, an effect which may contribute to the global benefit of tPA-based stroke treatment.
Stroke and the immune system: from pathophysiology to new therapeutic strategies.
Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, Dirnagl U, Vivien D
Lancet Neurol 1474-4465
PMID : 21511199
KEYWORDS : Animals|Brain|drug effects|Brain Diseases|immunology|Humans|Immunologic Factors|therapeutic use|Stroke|immunology
Show abstract [+]
Stroke is the second most common cause of death worldwide and a major cause of acquired disability in adults. Despite tremendous progress in understanding the pathophysiology of stroke, translation of this knowledge into effective therapies has largely failed, with the exception of thrombolysis, which only benefits a small proportion of patients. Systemic and local immune responses have important roles in causing stroke and are implicated in the primary and secondary progression of ischaemic lesions, as well as in repair, recovery, and overall outcome after a stroke. However, potential therapeutic targets in the immune system and inflammatory responses have not been well characterised. Development of novel and effective therapeutic strategies for stroke will require further investigation of these pathways in terms of their temporal profile (before, during, and after stroke) and risk-to-benefit therapeutic ratio of modulating them.
Enriched housing reverses age-associated impairment of cognitive functions and tPA-dependent maturation of BDNF.
Obiang P, Maubert E, Bardou I, Nicole O, Launay S, Bezin L, Vivien D, Agin V
Neurobiol Learn Mem 1095-9564
PMID : 21440650
KEYWORDS : Aging|physiology|Animals|Association Learning|physiology|Behavior, Animal|physiology|Brain|physiology|Brain-Derived Neurotrophic Factor|metabolism|Conditioning, Psychological|physiology|Environment|Fear|physiology|Female|Housing, Animal|Memory|physiology|Mice|Neurons|physiology|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Although tissue type plasminogen activator (tPA) and brain derived neurotrophic factor (BDNF) have been extensively described to influence brain outcomes in a number of disorders, their roles during physiological aging are poorly investigated. In the present study, we investigated whether maintenance of mice in different environmental conditions could influence age-associated changes in hippocampal tPA expression and BDNF maturation in relation with modifications of their cognitive performances. Our data indicate that maintenance in enriched housing led to a reversal of age-associated decrease in expression of hippocampal tPA. A subsequent increase in the level of mature BDNF and an improvement in emotional and spatial memories were observed. Taken together, these data suggest that the tPA-BDNF axis could play a critical role in the control of cognitive functions influenced both by the age and housing conditions.
2010
Functional occurrence of the interaction of tissue plasminogen activator with the NR1 Subunit of N-methyl-D-aspartate receptors during stroke.
Macrez R, Bezin L, Le Mauff B, Ali C, Vivien D
Stroke 1524-4628
PMID : 20966414
KEYWORDS : Animals|Autoantibodies|biosynthesis|Immunization|Immunohistochemistry|Mice|Nerve Tissue Proteins|biosynthesis|Receptors, N-Methyl-D-Aspartate|genetics|Recombinant Proteins|biosynthesis|Stroke|drug therapy|Thrombin|pharmacology|Thrombolytic Therapy|Tissue Plasminogen Activator|immunology
Show abstract [+]
Despite its fibrinolytic effect, tissue-type plasminogen activator (tPA) displays deleterious effects in the brain, including proexcitotoxicity, that can reduce the overall benefit from thrombolysis during stroke. We have proposed that tPA potentiates excitotoxicity by interacting with and cleaving the aminoterminal end of the NR1 subunit of N-methyl-d-aspartate receptors, leading to an increased calcium influx, Erk1/2 activation, and neurotoxicity. Because this mechanism is debated, our aim was to demonstrate its in vivo occurrence and relevance. Because tPA is released under ischemic conditions, we hypothesized that if it indeed processes NR1, then the released fragment should reactivate the immune system in animals that had been immunized long before with recombinant aminoterminal end of the NR1. This effect should be exacerbated in ischemic animals thrombolysed with recombinant tPA.
Plasmin on adherent cells: from microvesiculation to apoptosis.
Doeuvre L, Plawinski L, Goux D, Vivien D, Anglés-Cano E
Biochem J 1470-8728
PMID : 20846121
KEYWORDS : Animals|Apoptosis|Blood Platelets|cytology|Blotting, Western|CHO Cells|Cell Adhesion|physiology|Cell Survival|physiology|Cricetinae|Cricetulus|Fibrinolysin|biosynthesis|Humans|In Situ Nick-End Labeling|Kinetics|Microscopy, Electron|Plasminogen|chemistry|Tissue Plasminogen Activator|physiology
Show abstract [+]
Cell activation by stressors is characterized by a sequence of detectable phenotypic cell changes. A given stimulus, depending on its strength, induces modifications in the activity of membrane phospholipid transporters and calpains, which lead to phosphatidylserine exposure, membrane blebbing and the release of microparticles (nanoscale membrane vesicles). This vesiculation could be considered as a warning signal that may be followed, if the stimulus is maintained, by cell detachment-induced apoptosis. In the present study, plasminogen incubated with adherent cells is converted into plasmin by constitutively expressed tPA (tissue-type plasminogen activator) or uPA (urokinase-type plasminogen activator). Plasmin formed on the cell membrane then induces a unique response characterized by membrane blebbing and vesiculation. Hitherto unknown for plasmin, these membrane changes are similar to those induced by thrombin on platelets. If plasmin formation persists, matrix proteins are then degraded, cells lose their attachments and enter the apoptotic process, characterized by DNA fragmentation and specific ultrastructural features. Since other proteolytic or inflammatory stimuli may evoke similar responses in different types of adherent cells, the proposed experimental procedure can be used to distinguish activated adherent cells from cells entering the apoptotic process. Such a distinction is crucial for evaluating the effects of mediators, inhibitors and potential therapeutic agents.
Tissue-type plasminogen activator induces plasmin-dependent proteolysis of intracellular neuronal nitric oxide synthase.
Baron A, Hommet Y, Cassé F, Vivien D
Biol Cell 1768-322X
PMID : 20636282
KEYWORDS : Animals|Fibrinolysin|metabolism|Mice|N-Methylaspartate|metabolism|Neurons|enzymology|Nitric Oxide Synthase Type I|metabolism|Signal Transduction|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Despite its pro-fibrinolytic activity, tPA (tissue plasminogen activator) is a serine protease known to influence a number of physiological and pathological functions in the central nervous system. Accordingly, tPA was reported to mediate some of its functions in the central nervous system through NMDA (N-methyl-D-aspartate) receptors, LRP (low-density lipoprotein receptor-related protein) or annexin II.
NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity.
Baron A, Montagne A, Cassé F, Launay S, Maubert E, Ali C, Vivien D
Cell Death Differ 1476-5403
PMID : 19911010
KEYWORDS : Animals|Cells, Cultured|Diazonium Compounds|pharmacology|Fibrinolytic Agents|pharmacology|Immunoblotting|Immunohistochemistry|Mice|Neurons|drug effects|Potassium Chloride|pharmacology|Pyridines|pharmacology|RNA Interference|Receptors, N-Methyl-D-Aspartate|genetics|Reverse Transcriptase Polymerase Chain Reaction|Tissue Plasminogen Activator|pharmacology
Show abstract [+]
Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S(*), 3R(*))-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDAR-dependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.
2009
[Cerebral ischemia (2), How to neutralize the neurotoxic effects of tPA].
Vivien D, Gauberti M, Guedin P, Anglés-Cano E,
Med Sci (Paris) 0767-0974
PMID : 19849989
KEYWORDS : Amino Acid Sequence|Blood-Brain Barrier|Brain Ischemia|drug therapy|Humans|Molecular Sequence Data|Neurotoxins|toxicity|Thrombolytic Therapy|methods|Tissue Plasminogen Activator|chemistry
[Cellular microparticles, potential useful biomarkers in the identification of cerebrovascular accidents].
Anglés-Cano E, Vivien D,
Med Sci (Paris) 0767-0974
PMID : 19849987
KEYWORDS : Biomarkers|blood|Blood Coagulation|Cell-Derived Microparticles|metabolism|Fibrinolysis|Humans|Metalloproteases|blood|Stroke|blood
Show abstract [+]
The clinical utility of biomarkers depends on their ability to identify high-risk individuals in order to establish preventive, diagnostic or therapeutic measures. Currently, no practical, rapid and sensitive test is available for the diagnosis of acute ischemic stroke. A number of soluble molecules have been identified that are merely associated to these cerebrovascular accidents. Despite this association not a single molecule has the characteristics of a true biomarker directly involved in the pathophysiology of ischemic stroke-none of them is organ-specific and may therefore be elevated in the context of medical comorbidities. When explored as a combination of biomarkers, e.g. matrix metalloproteinase 9, brain natriuretic protein, D-dimer, protein S100B, the question still remains whether serial biomarker analysis provides additional prognostic information. Even S100B, a glial activation protein, has a low specificity for acute ischemic stroke because it may originate from extracranial sources. Current knowledge from the field of cell-derived microparticles suggests that these membrane fragments may represent reliable biomarkers as they are cell-specific and are released early in the pathophysiological cascade of a disease. These microparticles can be found not only in the cerebrospinal fluid but also in tears and circulating blood in case of blood-brain barrier dysfunction. They represent a new challenge in stroke diagnosis and management.
Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact.
Roussel BD, Macrez R, Jullienne A, Agin V, Maubert E, Dauphinot L, Potier MC, Plawinski L, Castel H, Hommet Y, Munuera J, Montaner J, Yepes M, Ali C, Vivien D
Brain 1460-2156
PMID : 19574439
KEYWORDS : Aged|Aged, 80 and over|Aging|metabolism|Animals|Brain|metabolism|Brain Ischemia|metabolism|Cell Death|drug effects|DNA-Binding Proteins|genetics|Disease Models, Animal|Female|Gene Knockdown Techniques|methods|Humans|Magnetic Resonance Imaging|methods|Mice|Mice, Inbred C57BL|Middle Aged|N-Methylaspartate|toxicity|Neurons|drug effects|Reverse Transcriptase Polymerase Chain Reaction|methods|Tissue Plasminogen Activator|metabolism|Transcription Factors|genetics
Show abstract [+]
Recombinant tissue-type plasminogen activator (tPA) is the fibrinolytic drug of choice to treat stroke patients. However, a growing body of evidence indicates that besides its beneficial thrombolytic role, tPA can also have a deleterious effect on the ischaemic brain. Although ageing influences stroke incidence, complications and outcome, age-dependent relationships between endogenous tPA and stroke injuries have not been investigated yet. Here, we report that ageing is associated with a selective lowering of brain tPA expression in the murine brain. Moreover, our results show that albumin D site-binding protein (DBP) as a key age-associated regulator of the neuronal transcription of tPA. Additionally, inhibition of DBP-mediated tPA expression confers in vitro neuroprotection. Accordingly, reduced levels of tPA in old mice are associated with smaller excitotoxic/ischaemic injuries and protection of the permeability of the neurovascular unit during cerebral ischaemia. Likewise, we provide neuroradiological evidence indicating the existence of an inverse relationship between age and the volume of the ischaemic lesion in patients with acute ischaemic stroke. Together, these results indicate that the relationship among DBP, tPA and ageing play an important role in the outcome of cerebral ischaemia.
Distribution of oxytocin-like and vasopressin-like immunoreactivities within the central nervous system of the cuttlefish, Sepia officinalis.
Bardou I, Maubert E, Leprince J, Chichery R, Cocquerelle C, Launay S, Vivien D, Vaudry H, Agin V
Cell Tissue Res 1432-0878
PMID : 19259702
KEYWORDS : Amino Acid Sequence|Animals|Central Nervous System|anatomy & histology|Mice|Molecular Sequence Data|Nerve Fibers|metabolism|Oxytocin|chemistry|Sepia|metabolism|Vasopressins|chemistry
Show abstract [+]
We have investigated the distribution of oxytocin/vasopressin (OT/VP) superfamily peptides in the central nervous system (CNS) of the cuttlefish, Sepia officinalis, by using antibodies raised against mammalian OT and VP. Several populations of OT-like and VP-like immunoreactive cell bodies and fibers were widely distributed in cerebral structures involved in learning processes (vertical lobe complex, optic lobes), behavioral communication (peduncle, lateral basal and chromatophore lobes), feeding behavior (inferior frontal, brachial and buccal lobes), sexual activity (dorsal basal, subpedunculate, olfactory lobes), and metabolism (visceral lobes). The two most remarkable findings of this study were the occurrence of OT-like immunoreactivity in many amacrine cells of the vertical lobe and the dense accumulation of VP-like immunoreactive cell bodies in the subpedunculate 1 lobe. No double-immunolabeled cell bodies or fibers were found in any lobes of the CNS, indicating, for the first time in a decapod cephalopod mollusc, the existence of distinct oxytocinergic-like and vasopressinergic-like systems. The widespread distribution of the immunoreactive neurons suggests that these OT-like and VP-like peptides act as neurotransmitters or neuromodulators.
2008
HtrA1-dependent proteolysis of TGF-beta controls both neuronal maturation and developmental survival.
Launay S, Maubert E, Lebeurrier N, Tennstaedt A, Campioni M, Docagne F, Gabriel C, Dauphinot L, Potier MC, Ehrmann M, Baldi A, Vivien D
Cell Death Differ 1350-9047
PMID : 18551132
KEYWORDS : Animals|Brain|embryology|Cell Survival|Cells, Cultured|High-Temperature Requirement A Serine Peptidase 1|Mice|Mice, Transgenic|Neurons|cytology|Serine Endopeptidases|metabolism|Signal Transduction|Transforming Growth Factor beta1|metabolism|Up-Regulation
Show abstract [+]
Transforming growth factor-beta (TGF-beta) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-beta accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice overexpressing a TGF-beta-responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-beta signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-beta1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-beta signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-beta could be one of the critical events controlling both neuronal maturation and developmental survival.
Toward safer thrombolytic agents in stroke: molecular requirements for NMDA receptor-mediated neurotoxicity.
Lopez-Atalaya JP, Roussel BD, Levrat D, Parcq J, Nicole O, Hommet Y, Benchenane K, Castel H, Leprince J, To Van D, Bureau R, Rault S, Vaudry H, Petersen KU, Santos JS, Ali C, Vivien D
J Cereb Blood Flow Metab 0271-678X
PMID : 18334994
KEYWORDS : Amino Acid Sequence|Animals|Catalytic Domain|Cells, Cultured|Drug-Related Side Effects and Adverse Reactions|Fibrinolytic Agents|toxicity|Mice|Models, Molecular|Molecular Sequence Data|Neurons|drug effects|Plasminogen Activators|metabolism|Protein Binding|Protein Structure, Quaternary|Receptors, N-Methyl-D-Aspartate|chemistry|Signal Transduction|Stroke|metabolism|Tissue Culture Techniques|Tissue Plasminogen Activator|chemistry
Show abstract [+]
Current thrombolytic therapy for acute ischemic stroke with tissue-type plasminogen activator (tPA) has clear global benefits. Nevertheless, evidences argue that in addition to its prohemorrhagic effect, tPA might enhance excitotoxic necrosis. In the brain parenchyma, tPA, by binding to and then cleaving the amino-terminal domain (ATD) of the NR1 subunit of N-methyl-D-aspartate (NMDA) glutamate receptors, increases calcium influx to toxic levels. We show here that tPA binds the ATD of the NR1 subunit by a two-sites system (K(D)=24 nmol/L). Although tenecteplase (TNK) and reteplase also display two-sites binding profiles, the catalytically inactive mutant TNKS478A displays a one-site binding profile and desmoteplase (DSPA), a kringle 2 (K2) domain-free plasminogen activator derived from vampire bat, does not interact with NR1. Moreover, we show that in contrast to tPA, DSPA does not promote excitotoxicity. These findings, together with three-dimensional (3D) modeling, show that a critical step for interaction of tPA with NR1 is the binding of its K2 domain, followed by the binding of its catalytic domain, which in turn cleaves the NR1 subunit at its ATD, leading to a subsequent potentiation of NMDA-induced calcium influx and neurotoxicity. This could help design safer new generation thrombolytic agents for stroke treatment.
2007
Neuroprotection and stroke: time for a compromise.
Young AR, Ali C, Duretête A, Vivien D
J Neurochem 1471-4159
PMID : 17727635
KEYWORDS : Animals|Clinical Trials as Topic|trends|Humans|Neuroprotective Agents|therapeutic use|Stroke|drug therapy|Thrombolytic Therapy|methods
Show abstract [+]
In April 2007, there existed a repertory of 286 trials concerned with acute ischemic stroke on the Stroke Trials Registry (http://www.strokecenter.org/trials/), of which 209 trials were considered as complete (with no evidence of patient benefit unless one considers the much hard fought for and modest results of the tPA studies). Among other questions arising from such failures, one can wonder whether the plethora of pharmacological agents that exhibited neuroprotective properties in pre-clinical studies were selected for clinical trials entirely based upon their experimental efficacy. This mini-review will try to point out some of the weaknesses that could underline the failure of both researchers and clinicians involved in the field of stroke to obtain their ultimate goal--brain protection.
Mouse model of in situ thromboembolic stroke and reperfusion.
Orset C, Macrez R, Young AR, Panthou D, Angles-Cano E, Maubert E, Agin V, Vivien D
Stroke 1524-4628
PMID : 17702959
KEYWORDS : Animals|Cerebral Infarction|chemically induced|Cerebrovascular Circulation|drug effects|Disease Models, Animal|Fibrinolytic Agents|pharmacology|Intracranial Embolism|chemically induced|Laser-Doppler Flowmetry|Male|Mice|Motor Activity|Reperfusion|Reproducibility of Results|Thrombin|Tissue Plasminogen Activator|pharmacology
Show abstract [+]
Early reperfusion using tissue-type plasminogen activator is the only therapeutic agent to treat focal cerebral ischemia with proven efficacy in patients. Nevertheless, novel insights into the pathophysiology of neurons, glial cells, and the fate of the endothelium after stroke call for the use of new strategies to improve stroke treatment alone or in combination with tissue-type plasminogen activator-induced thrombolysis. Unfortunately, despite the plethora of drugs that display clear beneficial effects in animal models of experimental ischemia, their subsequent use in clinical trials has proven disappointing. As such, one is forced to consider that new animal models of focal cerebral ischemia may be required before clinical evaluation of a new molecule.
Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms.
Cacquevel M, Launay S, Castel H, Benchenane K, Chéenne S, Buée L, Moons L, Delacourte A, Carmeliet P, Vivien D
Neurobiol Dis 0969-9961
PMID : 17566751
KEYWORDS : Aging|physiology|Alzheimer Disease|enzymology|Amyloid beta-Peptides|metabolism|Animals|Brain|enzymology|Enzyme-Linked Immunosorbent Assay|Humans|Immunohistochemistry|Mice|Mice, Transgenic|RNA, Messenger|analysis|Reverse Transcriptase Polymerase Chain Reaction|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Alzheimer's disease (AD) is the most common form of neurodegenerative disorder in the ageing population. It is characterized by the cerebral accumulation of toxic amyloid-beta peptide assemblies (Abeta). The serine protease plasmin, which is generated from the inactive zymogen plasminogen through its proteolytic cleavage by tissue- (tPA) or urokinase-type plasminogen activator, has been implicated in the catabolism of Abeta peptides. In this report, we studied the regulation of tPA activity in vivo during ageing in normal mice and in a mouse model of AD characterized by an exacerbated endogenous Abeta accumulation. We observed that cerebral tPA activity was decreased during ageing in normal mice and that this effect was worsened in mice overproducing Abeta peptides. These phenomena result, respectively, from a decrease in tPA expression and from an increase in the production of one of the tPA inhibitors, the plasminogen activator inhibitor type 1 (PAI-1). A similar study in sporadic AD and age-matched control brain tissues revealed that the tPA proteolytic activity was negatively correlated to Abeta peptides levels supporting the data observed in mice. Altogether, our data support a model in which amyloid deposition induces a decrease in tPA activity through the overproduction of PAI-1 by activated glial cells.
Recombinant Desmodus rotundus salivary plasminogen activator crosses the blood-brain barrier through a low-density lipoprotein receptor-related protein-dependent mechanism without exerting neurotoxic effects.
López-Atalaya JP, Roussel BD, Ali C, Maubert E, Petersen KU, Berezowski V, Cecchelli R, Orset C, Vivien D
Stroke 1524-4628
PMID : 17325305
KEYWORDS : Animals|Blood-Brain Barrier|drug effects|Cattle|Cells, Cultured|Chiroptera|Coculture Techniques|Fibrinolytic Agents|pharmacokinetics|Humans|Low Density Lipoprotein Receptor-Related Protein-1|physiology|Male|Plasminogen Activators|pharmacokinetics|Rats|Rats, Sprague-Dawley|Recombinant Proteins|pharmacokinetics
Show abstract [+]
Desmoteplase, a recombinant form of the plasminogen activator DSPAalpha1 from Desmodus rotundus, may offer improved clinical benefits for acute ischemic stroke treatment over the current therapy, recombinant tissue plasminogen activator (rtPA). Accumulating evidence suggests that clinical use of rtPA could be limited by unfavorable properties, including its ability to cross the blood-brain barrier (BBB), thus potentially adding to the pro-excitotoxic effect of endogenous tPA in cerebral parenchyma. Here, to investigate whether desmoteplase may display a safer profile than the structurally-related tPA, both agents were compared for their ability to cross the BBB and promote neurotoxicity.
Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory.
Benchenane K, Castel H, Boulouard M, Bluthé R, Fernandez-Monreal M, Roussel BD, Lopez-Atalaya JP, Butt-Gueulle S, Agin V, Maubert E, Dantzer R, Touzani O, Dauphin F, Vivien D, Ali C
J Cell Sci 0021-9533
PMID : 17244650
KEYWORDS : Animals|Behavior, Animal|drug effects|Excitatory Amino Acid Agonists|pharmacology|Female|Maze Learning|drug effects|Memory|drug effects|Mice|Models, Immunological|N-Methylaspartate|pharmacology|Protein Structure, Tertiary|Receptors, N-Methyl-D-Aspartate|chemistry|Tissue Plasminogen Activator|deficiency|Vaccination
Show abstract [+]
Fine-tuning of NMDA glutamatergic receptor signalling strategically controls crucial brain functions. This process depends on several ligands and modulators, one of which unexpectedly includes the serine protease tissue-type plasminogen activator (tPA). In vitro, tPA increases NMDA-receptor-mediated calcium influx by interacting with, and then cleaving, the NR1 subunit within its N-terminal domain. Owing to lack of in vivo evidence of the relevance and contribution of this mechanism in physiological and pathological brain processes, active immunisation was developed here in mice, to allow transient and specific prevention of the interaction of tPA with the NR1 subunit. Immunisation significantly reduced the severity of ischemic and excitotoxic insults in the mouse brain. Cognitive function was altered in some, but not all behavioural tasks affected in tPA-deficient mice. Our data demonstrate that in vivo, tPA controls neurotoxicity and the encoding of novel spatial experiences by binding to and cleaving the NMDA receptor NR1 subunit. Interesting therapeutic possibilities for several brain pathologies that involve excitotoxicity may now be envisaged.
2006
Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity.
Liot G, Roussel BD, Lebeurrier N, Benchenane K, López-Atalaya JP, Vivien D, Ali C
J Neurochem 0022-3042
PMID : 16800849
KEYWORDS : Analysis of Variance|Animals|Apoptosis|drug effects|Blotting, Western|methods|Butadienes|pharmacology|Cell Count|methods|Cerebral Cortex|cytology|Chromones|pharmacology|Dose-Response Relationship, Drug|Drug Administration Schedule|Drug Interactions|Embryo, Mammalian|Enzyme Inhibitors|Fibrinolytic Agents|pharmacology|Immunohistochemistry|methods|Mice|Morpholines|pharmacology|Neurons|drug effects|Neuropeptides|pharmacology|Nitriles|pharmacology|Nuclear Proteins|pharmacology|Serpins|pharmacology|Serum|physiology|Time Factors|Tissue Plasminogen Activator|administration & dosage|Neuroserpin
Show abstract [+]
Although the mechanism of action of tissue-type plasminogen activator (tPA) in excitotoxic necrosis is well documented, whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly, blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly, prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly, the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology.
Transforming growth factor-beta signalling in brain disorders.
Vivien D, Ali C
Cytokine Growth Factor Rev 1359-6101
PMID : 16271500
KEYWORDS : Animals|Brain Diseases|drug therapy|Disease Progression|Humans|Receptors, Transforming Growth Factor beta|physiology|Signal Transduction|physiology|Transforming Growth Factor beta|physiology
Show abstract [+]
Transforming growth factor-beta (TGF-beta) has been characterized as an injury-related factor, based on the observation that it is strongly up-regulated in many acute or chronic central nervous system disorders. TGF-beta is generally thought to be neuroprotective and several mechanisms have been proposed to explain this beneficial action. For instance, TGF-beta protects neurons against the potentiating effect of tissue-type plasminogen activator on NMDA receptor-mediated excitotoxicity, by up-regulating type-1 plasminogen activator inhibitor expression in astrocytes. TGF-beta has also anti-apoptotic properties, through a recruitment of a mitogen-activated protein kinase pathway and a concomitant activation of anti-apoptotic members of the Bcl-2 family. These multiple mechanisms might reflect the pleiotropic nature of TGF-beta, reinforcing the potential therapeutic value of this cytokine in several central nervous system disorders.
2005
The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo.
Lebeurrier N, Liot G, Lopez-Atalaya JP, Orset C, Fernandez-Monreal M, Sonderegger P, Ali C, Vivien D
Mol Cell Neurosci 1044-7431
PMID : 16209928
KEYWORDS : Animals|Apoptosis|drug effects|Brain|drug effects|Brain Ischemia|drug therapy|Calcium Signaling|drug effects|Cells, Cultured|Cerebral Cortex|drug effects|Corpus Striatum|drug effects|Disease Models, Animal|Male|Mice|N-Methylaspartate|antagonists & inhibitors|Neurons|drug effects|Neuropeptides|metabolism|Neuroprotective Agents|metabolism|Neurotoxins|antagonists & inhibitors|Receptors, N-Methyl-D-Aspartate|drug effects|Serpins|metabolism|Stroke|metabolism|Neuroserpin
Show abstract [+]
Considering its brain-specific expression, neuroserpin (NS), a potent inhibitor of tissue-type plasminogen activator (tPA), might be a good therapeutic target to limit the pro-excitotoxic effects of tPA within the cerebral parenchyma, without affecting the benefit from thrombolysis in stroke patients. Here, we aimed at determining the mechanisms of action responsible for the previously reported neuroprotective activity of NS in rodent experimental cerebral ischemia. First, we show in vivo that exogenous NS protects the cortex and the striatum against NMDA-induced injury. Then, the cellular mechanisms of this neuroprotection were investigated in primary cultures of cortical neurons. We show that NS fails to prevent serum deprivation-induced apoptotic neuronal death, while it selectively prevents NMDA- but not AMPA-induced excitotoxicity. This beneficial effect is associated to a decrease in NMDA receptor-mediated intracellular calcium influx. Altogether, these data suggest that an overexpression of neuroserpin in the brain parenchyma might limit the deleterious effect of tPA on NMDA receptor-mediated neuronal death, which occurs following experimental ischemia.
Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis.
Benchenane K, Berezowski V, Ali C, Fernández-Monreal M, López-Atalaya JP, Brillault J, Chuquet J, Nouvelot A, MacKenzie ET, Bu G, Cecchelli R, Touzani O, Vivien D
Circulation 1524-4539
PMID : 15851587
KEYWORDS : Animals|Blood-Brain Barrier|metabolism|Brain|drug effects|Cold Temperature|Low Density Lipoprotein Receptor-Related Protein-1|metabolism|Male|N-Methylaspartate|administration & dosage|Neurotoxicity Syndromes|etiology|Plasminogen Activator Inhibitor 1|administration & dosage|Protein Transport|Rats|Rats, Sprague-Dawley|Tissue Plasminogen Activator|adverse effects
Show abstract [+]
Accumulating evidence demonstrates a critical involvement of tissue-type plasminogen activator (tPA) in pathological and physiological brain conditions. Determining whether and how vascular tPA can cross the blood-brain barrier (BBB) to enter the brain is thus important, not only during stroke but also in physiological conditions.
Oxygen glucose deprivation switches the transport of tPA across the blood-brain barrier from an LRP-dependent to an increased LRP-independent process.
Benchenane K, Berezowski V, Fernández-Monreal M, Brillault J, Valable S, Dehouck MP, Cecchelli R, Vivien D, Touzani O, Ali C
Stroke 1524-4628
PMID : 15817895
KEYWORDS : Animals|Blood-Brain Barrier|metabolism|Brain Ischemia|etiology|Cell Hypoxia|Cytoplasmic Vesicles|chemistry|Endothelium, Vascular|cytology|Glucose|physiology|Infarction, Middle Cerebral Artery|complications|LDL-Receptor Related Proteins|antagonists & inhibitors|Male|Mice|Protein Transport|Tissue Plasminogen Activator|analysis
Show abstract [+]
Despite uncontroversial benefit from its thrombolytic activity, the documented neurotoxic effect of tissue plasminogen activator (tPA) raises an important issue: the current emergency stroke treatment might not be optimum if exogenous tPA can enter the brain and thus add to the deleterious effects of endogenous tPA within the cerebral parenchyma. Here, we aimed at determining whether vascular tPA crosses the blood-brain barrier (BBB) during cerebral ischemia, and if so, by which mechanism.
Akt-dependent expression of NAIP-1 protects neurons against amyloid-{beta} toxicity.
Lesné S, Gabriel C, Nelson DA, White E, Mackenzie ET, Vivien D, Buisson A
J Biol Chem 0021-9258
PMID : 15797869
KEYWORDS : Amyloid beta-Peptides|toxicity|Animals|Apoptosis|Blotting, Western|Brain|metabolism|Caspase 3|Caspase 8|Caspase 9|Caspases|metabolism|Cells, Cultured|Chromones|pharmacology|DNA|chemistry|Densitometry|Dose-Response Relationship, Drug|Electrophoresis, Agar Gel|methods|Enzyme Activation|Enzyme Inhibitors|pharmacology|Immunohistochemistry|Immunoprecipitation|Mice|Microscopy, Fluorescence|Morpholines|pharmacology|Nerve Tissue Proteins|metabolism|Neuronal Apoptosis-Inhibitory Protein|Neurons|metabolism|Phosphatidylinositol 3-Kinases|metabolism|Phosphorylation|Protein Serine-Threonine Kinases|metabolism|Proto-Oncogene Proteins|metabolism|Proto-Oncogene Proteins c-akt|Signal Transduction|Time Factors|Up-Regulation
Show abstract [+]
Neurotrophins are a family of growth factors that attenuate several forms of pathological neuronal cell death and may represent a putative therapeutic approach to neurodegenerative diseases. In Alzheimer disease, amyloid-beta (Abeta) is thought to play a central role in the neuronal death occurring in brains of patients. In the present study, we evaluate the ability of neurotrophin-3 (NT-3) to protect neurons against the toxicity induced by aggregated Abeta. We showed that in primary cultures of cortical neurons, NT-3 reduces Abeta-induced apoptosis by limiting caspase-8, caspase-9, and caspase-3 cleavage. This neuroprotective effect of NT-3 was concomitant to an increased level of Akt phosphorylation and was abolished by an inhibitor of the phosphatidylinositol-3 kinase (PI-3K), LY294002. In parallel, NT-3 treatment reduced Abeta induced caspase-3 processing to control levels. In an attempt to link PI-3K/Akt to caspase inhibition, we evaluated the influence of the PI-3K/Akt axis on the expression of a member of the inhibitors of apoptosis proteins (IAPs), the neuronal apoptosis inhibitory protein-1. We demonstrated that NT-3 induces an up-regulation of neuronal apoptosis inhibitory protein-1 expression in neurons that promotes the inhibition of Abeta-induced neuronal apoptosis. Together, these findings demonstrate that NT-3 signaling counters Abeta-dependent neuronal cell death and may represent an innovative therapeutic intervention to limit neuronal death in Alzheimer disease.
2004
2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one dihydrochloride, tPA stop, prevents tPA-enhanced excitotoxicity both in vitro and in vivo.
Liot G, Benchenane K, Léveillé F, López-Atalaya JP, Fernández-Monreal M, Ruocco A, Mackenzie ET, Buisson A, Ali C, Vivien D
J Cereb Blood Flow Metab 0271-678X
PMID : 15529015
KEYWORDS : Animals|Brain Ischemia|drug therapy|Cell Death|drug effects|Cells, Cultured|Cycloheptanes|Excitatory Amino Acid Agonists|toxicity|In Vitro Techniques|Male|Mice|N-Methylaspartate|toxicity|Neurons|cytology|Neurotoxins|toxicity|Rats|Rats, Sprague-Dawley|Serine Proteinase Inhibitors|pharmacology|Signal Transduction|drug effects|Tissue Plasminogen Activator|antagonists & inhibitors
Show abstract [+]
Tissue-type plasminogen activator (tPA) is available for the treatment of thromboembolic stroke in humans. However, adverse effects of tPA have been observed in animal models of ischemic brain injuries. In the present study, we have used a synthetic tPA inhibitor, named 2,7-bis-(4-amidino-benzylidene)-cycloheptan-1-one dihydrochloride (tPA stop), to investigate the role of endogenous tPA in the cerebral parenchyma. In mouse cortical cell cultures, we observed that although tPA stop reduced N-methyl-D-aspartic acid (NMDA)-mediated excitotoxic neuronal death, it failed to modulate alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazole propanoic acid or kainate-mediated necrosis. In addition, we found that tPA stop could prevent the deleterious effects of both endogenous and exogenous tPA during NMDA exposure. At the functional level, tPA stop was found to prevent tPA-dependent potentiation of NMDA receptor-evoked calcium influx. The relevance of those findings was strengthened by the observation of a massive reduction of NMDA-induced excitotoxic lesion in rats when tPA stop was co-injected. Altogether, these data demonstrate that the blockade of the endogenous proteolytic activity of tPA in the cerebral parenchyma could be a powerful neuroprotective strategy raised against brain pathologies associated with excitotoxicity.
Arginine 260 of the amino-terminal domain of NR1 subunit is critical for tissue-type plasminogen activator-mediated enhancement of N-methyl-D-aspartate receptor signaling.
Fernández-Monreal M, López-Atalaya JP, Benchenane K, Cacquevel M, Dulin F, Le Caer JP, Rossier J, Jarrige AC, Mackenzie ET, Colloc'h N, Ali C, Vivien D
J Biol Chem 0021-9258
PMID : 15448144
KEYWORDS : Alanine|chemistry|Amino Acid Sequence|Animals|Arginine|chemistry|Binding Sites|Calcium|chemistry|Cell Line|Humans|Immunoblotting|Kinetics|Ligands|Mass Spectrometry|Mice|Microscopy, Video|Models, Molecular|Molecular Sequence Data|Mutagenesis, Site-Directed|Mutation|Neurons|metabolism|Point Mutation|Protein Binding|Protein Conformation|Protein Structure, Tertiary|Receptors, N-Methyl-D-Aspartate|chemistry|Recombinant Proteins|chemistry|Sequence Homology, Amino Acid|Signal Transduction|Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization|Temperature|Time Factors|Tissue Plasminogen Activator|chemistry|Transfection
Show abstract [+]
Tissue-type plasminogen activator (tPA) has been involved in both physiological and pathological glutamatergic-dependent processes, such as synaptic plasticity, seizure, trauma, and stroke. In a previous study, we have shown that the proteolytic activity of tPA enhances the N-methyl-D-aspartate (NMDA) receptor-mediated signaling in neurons (Nicole, O., Docagne, F., Ali, C., Margaill, I., Carmeliet, P., MacKenzie, E. T., Vivien, D., and Buisson, A. (2001) Nat. Med. 7, 59-64). Here, we show that tPA forms a direct complex with the amino-terminal domain (ATD) of the NR1 subunit of the NMDA receptor and cleaves this subunit at the arginine 260. Furthermore, point mutation analyses show that arginine 260 is necessary for both tPA-induced cleavage of the ATD of NR1 and tPA-induced potentiation of NMDA receptor signaling. Thus, tPA is the first binding protein described so far to interact with the ATD of NR1 and to modulate the NMDA receptor function.
Cytokines in neuroinflammation and Alzheimer's disease.
Cacquevel M, Lebeurrier N, Chéenne S, Vivien D
Curr Drug Targets 1389-4501
PMID : 15270199
KEYWORDS : Alzheimer Disease|metabolism|Brain|cytology|Cytokines|chemistry|Humans|Inflammation|metabolism|Models, Biological|Transforming Growth Factor beta|chemistry
Show abstract [+]
Inflammation has been reported in numerous neurodegenerative disorders such as Parkinson's disease, stroke and Alzheimer's disease (AD). In AD, the inflammatory response is mainly located to the vicinity of amyloid plaques. Cytokines, such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-alpha) and Transforminng Growth Factor beta (TGF-beta) have been clearly involved in this inflammatory process. Although their expression is induced by the presence of amyloid-beta peptide, these cytokines are also able to promote the accumulation of amyloid-beta peptide. Altogether, IL-1, IL-6, TNF-alpha and TGF-beta should be considered as key players of a vicious circle leading to the progression of the disease.
The complexity of tissue-type plasminogen activator: can serine protease inhibitors help in stroke management?
Lebeurrier N, Vivien D, Ali C
Expert Opin Ther Targets 1744-7631
PMID : 15268626
KEYWORDS : Animals|Disease Management|Humans|Serine Proteinase Inhibitors|administration & dosage|Stroke|drug therapy|Time Factors|Tissue Plasminogen Activator|administration & dosage
Show abstract [+]
Stroke, the third leading cause of death in industrialised countries, represents a major burden on healthcare authorities. The elucidation of molecular events sustaining infarct evolution in experimental models has allowed the development of putative therapeutic agents. However, despite marked benefits in animals, most of them have failed in clinical trials. At present, the only approved therapy for stroke is early reperfusion by intravenous injection of the thrombolytic agent, tissue-type plasminogen activator (tPA). tPA-dependent thrombolysis sometimes promotes haemorrhage, but improves neurological outcome in a great proportion of patients, provided it is performed within the recommended therapeutic window. In addition to the benefit of tPA injection in the vascular compartment, this endogenously produced serine protease could also promote excitotoxic processes within the cerebral parenchyma. This article reviews the various aspects of tPA during stroke, and discusses potential improvements to current clinical management, with a particular emphasis on targeting the deleterious actions of tPA through endogenous serine protease inhibitors (serpins).
Sp1 and Smad transcription factors co-operate to mediate TGF-beta-dependent activation of amyloid-beta precursor protein gene transcription.
Docagne F, Gabriel C, Lebeurrier N, Lesné S, Hommet Y, Plawinski L, Mackenzie ET, Vivien D
Biochem J 1470-8728
PMID : 15242331
KEYWORDS : Alzheimer Disease|genetics|Amyloid beta-Protein Precursor|genetics|Animals|Base Sequence|Cell Line|DNA-Binding Proteins|metabolism|Mink|Multiprotein Complexes|metabolism|Mutation|genetics|Protein Binding|drug effects|Response Elements|genetics|Signal Transduction|drug effects|Smad Proteins|Smad3 Protein|Smad4 Protein|Sp1 Transcription Factor|metabolism|Sp3 Transcription Factor|Trans-Activators|metabolism|Transcription Factors|metabolism|Transcription, Genetic|drug effects|Transcriptional Activation|drug effects|Transforming Growth Factor beta|pharmacology
Show abstract [+]
Abnormal deposition of Abeta (amyloid-beta peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-beta precursor protein). We have demonstrated previously that TGF-beta (transforming growth factor-beta), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Abeta. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-beta-dependent transcriptional activity. We report the following findings: first, TGF-beta is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named APP(TRE) (APP TGF-beta-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APP(TRE). We also observed that the APP(TRE) sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-beta-dependent activation of APP. TGF-beta signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-beta-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-beta in the regulation of Abeta production.
Neurotrophin-3-induced PI-3 kinase/Akt signaling rescues cortical neurons from apoptosis.
Liot G, Gabriel C, Cacquevel M, Ali C, MacKenzie ET, Buisson A, Vivien D
Exp Neurol 0014-4886
PMID : 15081586
KEYWORDS : Animals|Apoptosis|drug effects|Cells, Cultured|Cerebral Cortex|cytology|Culture Media, Serum-Free|pharmacology|Enzyme Inhibitors|pharmacology|MAP Kinase Signaling System|drug effects|Mice|Neurons|cytology|Neuroprotective Agents|pharmacology|Neurotrophin 3|pharmacology|Phosphatidylinositol 3-Kinases|metabolism|Phosphoinositide-3 Kinase Inhibitors|Protein Serine-Threonine Kinases|Proto-Oncogene Proteins|metabolism|Proto-Oncogene Proteins c-akt|Signal Transduction|drug effects
Show abstract [+]
A number of cytokines including neurotrophins have been tested for their neuroprotective activity against different paradigms of neuronal death. However, as for neurotrophin-3 (NT-3), their mechanisms of action have not been fully identified. By using cultures of mouse cortical neurons, we have investigated the molecular mechanisms by which neurotrophin-3 could protect cortical neurons against apoptosis. In a model of caspase-dependent apoptosis leading to the recruitment of active initiators caspase-8 and -9 and of executioner caspase-3, we have evidenced that NT-3 displayed an anti-apoptotic effect in a dose-dependent manner. First, we showed that, in cultured cortical neurons, NT-3 could promote extracellular signal-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) and phosphatidylinositol-3' (PI-3) kinase/Akt phosphorylation. Second, we showed that although the blockade of the Akt pathway prevented the anti-apoptotic effect of NT-3, blockade of the ERK pathway did not. Altogether, our data demonstrate that NT-3 displayed an anti-apoptotic effect on cultured cortical neurons through a mechanism involving the recruitment of the PI-3 kinase/Akt signaling pathway.
Is tissue-type plasminogen activator a neuromodulator?
Fernández-Monreal M, López-Atalaya JP, Benchenane K, Léveillé F, Cacquevel M, Plawinski L, MacKenzie ET, Bu G, Buisson A, Vivien D
Mol Cell Neurosci 1044-7431
PMID : 15080889
KEYWORDS : Action Potentials|drug effects|Animals|Brain|metabolism|Brain Chemistry|physiology|Calcium Signaling|drug effects|Cell Line|Cerebral Cortex|cytology|Chelating Agents|pharmacology|Exocytosis|drug effects|Glial Fibrillary Acidic Protein|metabolism|Humans|Low Density Lipoprotein Receptor-Related Protein-1|metabolism|Mice|Microtubule-Associated Proteins|metabolism|N-Methylaspartate|pharmacology|Neurons|drug effects|Neurotransmitter Agents|metabolism|Receptors, N-Methyl-D-Aspartate|agonists|Synaptic Transmission|drug effects|Tissue Plasminogen Activator|metabolism
Show abstract [+]
In the last few years, it has been evidenced that serine proteases play key roles in the mammalian brain, both in physiological and pathological conditions. It has been well established that among these serine proteases, the tissue-type plasminogen activator (t-PA) is critically involved in development, plasticity, and pathology of the nervous system. However, its mechanism of action remains to be further investigated. By using pharmacological and immunological approaches, we have evidenced in the present work that t-PA should be considered as a neuromodulator. Indeed, we have observed that: (i). neuronal depolarization induces a release of t-PA; (ii). this release of t-PA is sensitive to exocytosis inhibition and calcium chelation; (iii). released t-PA modulates NMDA receptor signaling and (iv). astrocytes are able to recapture extracellular t-PA through a low-density lipoprotein (LDL) receptor-related protein (LRP)-dependent mechanism.
Equivocal roles of tissue-type plasminogen activator in stroke-induced injury.
Benchenane K, López-Atalaya JP, Fernández-Monreal M, Touzani O, Vivien D
Trends Neurosci 0166-2236
PMID : 15036881
KEYWORDS : Animals|Cell Death|drug effects|Disease Models, Animal|Fibrinolytic Agents|adverse effects|Glutamic Acid|metabolism|Humans|Neuroglia|drug effects|Neurons|drug effects|Neuroprotective Agents|adverse effects|Signal Transduction|drug effects|Stroke|complications|Thrombolytic Therapy|methods|Tissue Plasminogen Activator|adverse effects|Transforming Growth Factor beta|therapeutic use|Transforming Growth Factor beta1
Show abstract [+]
Stroke represents a major health problem in the ever-ageing population of industrialized nations. Each year, over three million people in the USA alone suffer from this affliction. Stroke, which results from the obstruction of an intra- or extra-cerebral artery, induces irreversible neuronal damage. The clot-busting drug tissue-type plasminogen activator (tPA) is the only FDA-approved therapy for acute stroke. Although tPA has been successfully used to treat myocardial infarction due to clot formation, its use in the treatment of occlusive cerebrovascular diseases remains controversial. Indeed, tPA is clearly beneficial as a thrombolytic agent. However, increasing evidence suggests that tPA could have direct and deleterious effects on neurons and glial cells.
2003
Transforming growth factor-beta and ischemic brain injury.
Buisson A, Lesne S, Docagne F, Ali C, Nicole O, MacKenzie ET, Vivien D
Cell Mol Neurobiol 0272-4340
PMID : 14514014
KEYWORDS : Animals|Apoptosis|drug effects|Brain Infarction|drug therapy|Brain Ischemia|drug therapy|Carrier Proteins|metabolism|Humans|Mitogen-Activated Protein Kinases|metabolism|Neuroprotective Agents|metabolism|Plasminogen Activator Inhibitor 1|metabolism|Transforming Growth Factor beta|metabolism|Transforming Growth Factor beta1|bcl-Associated Death Protein
Show abstract [+]
1. Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by using the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. 2. Over the last years, the cytokine termed Transforming Growth Factor-beta1 (TGF-beta1) has been found to be strongly up-regulated in the central nervous system following ischemia-induced brain damage. 3. Recent studies have shown a neuroprotective activity of TGF-beta1 against ischemia-induced neuronal death. In vitro, TGF-beta1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes 4. In addition, TGF-beta1 has been recently characterized as an antiapoptotic factor in a model of staurosporine-induced neuronal death through a mechanism involving activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) and a concomitant increase phosphorylation of the antiapoptotic protein Bad. 5. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.
[Does transforming growth factor-beta (TGF-beta) act as a neuroprotective agent in cerebral ischemia?].
Docagne F, Ali C, Lesne S, Nicole O, MacKenzie ET, Buisson A, Vivien D
J Soc Biol 1295-0661
PMID : 12910629
KEYWORDS : Animals|Astrocytes|physiology|Brain Ischemia|genetics|Cell Death|drug effects|Gene Expression Regulation|Humans|Neuroprotective Agents|pharmacology|Plasminogen Activator Inhibitor 1|genetics|Transforming Growth Factor beta|pharmacology
Show abstract [+]
Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by means of the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. Over the last years, the cytokine termed Transforming Growth Factor-beta 1 (TGF-beta 1) has been found to be strongly up regulated in the central nervous system following ischemia-induced brain damage. Recent studies have shown a neuroprotective activity of TGF-beta 1 against ischemia-induced neuronal death. In vitro, TGF-beta 1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta 1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.
Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice.
Lesné S, Docagne F, Gabriel C, Liot G, Lahiri DK, Buée L, Plawinski L, Delacourte A, MacKenzie ET, Buisson A, Vivien D
J Biol Chem 0021-9258
PMID : 12626500
KEYWORDS : Alzheimer Disease|metabolism|Amyloid beta-Peptides|chemistry|Amyloid beta-Protein Precursor|genetics|Animals|Astrocytes|cytology|Base Sequence|Blotting, Western|Cell Nucleus|metabolism|Cells, Cultured|Culture Media, Conditioned|pharmacology|Densitometry|Enzyme-Linked Immunosorbent Assay|Genes, Reporter|Humans|Immunoblotting|Immunohistochemistry|Luciferases|metabolism|Mice|Mice, Inbred BALB C|Mice, Transgenic|Microglia|metabolism|Microscopy, Fluorescence|Molecular Sequence Data|Neurons|metabolism|Promoter Regions, Genetic|RNA, Messenger|metabolism|Reverse Transcriptase Polymerase Chain Reaction|Signal Transduction|Time Factors|Transcription Factors|Transfection|Transforming Growth Factor beta|chemistry|Transforming Growth Factor beta1|Transgenes
Show abstract [+]
Accumulation of the amyloid-beta peptide (Abeta) in the brain is crucial for development of Alzheimer's disease. Expression of transforming growth factor-beta1 (TGF-beta1), an immunosuppressive cytokine, has been correlated in vivo with Abeta accumulation in transgenic mice and recently with Abeta clearance by activated microglia. Here, we demonstrate that TGF-beta1 drives the production of Abeta40/42 by astrocytes leading to Abeta production in TGF-beta1 transgenic mice. First, TGF-beta1 induces the overexpression of the amyloid precursor protein (APP) in astrocytes but not in neurons, involving a highly conserved TGF-beta1-responsive element in the 5'-untranslated region (+54/+74) of the APP promoter. Second, we demonstrated an increased release of soluble APP-beta which led to TGF-beta1-induced Abeta generation in both murine and human astrocytes. These results demonstrate that TGF-beta1 potentiates Abeta production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients.
Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis.
Valable S, Bellail A, Lesné S, Liot G, Mackenzie ET, Vivien D, Bernaudin M, Petit E
FASEB J 1530-6860
PMID : 12514118
KEYWORDS : Angiogenesis Inducing Agents|pharmacology|Angiopoietin-1|Animals|Apoptosis|Cells, Cultured|Chromones|pharmacology|Culture Media, Serum-Free|Enzyme Activation|Enzyme Inhibitors|pharmacology|Membrane Glycoproteins|pharmacology|Mice|Models, Biological|Morpholines|pharmacology|Neoplasm Proteins|analysis|Neurons|cytology|Neuroprotective Agents|pharmacology|Phosphatidylinositol 3-Kinases|metabolism|Phosphoinositide-3 Kinase Inhibitors|Proto-Oncogene Proteins|Receptor, TIE-2
Show abstract [+]
Although angiopoietin-1 (Ang-1) is recognized as an endothelial growth factor, its presence in brain following an ischemic event suggests a role in the evolution of neuronal damage. Using primary neuronal cultures, we showed that neurons express Ang-1 and possess the functional angiopoietin-receptor Tie-2, which is phosphorylated in the presence of Ang-1. We further investigated in vitro whether Ang-1 could protect neurons against either excitotoxic necrosis or apoptosis induced by serum deprivation (SD). A neuroprotective effect for Ang-1 was detected exclusively in the apoptotic paradigm. Treatment of cells with the phosphatidyl-inositol 3-kinase (PI3-K) inhibitor, LY294002, inhibited Ang-1-induced phosphorylation of Akt, restored the cleavage of the effector caspase-3, and reduced the protective effect of Ang-1 against SD-induced toxicity. These findings suggest that Ang-1 has a neuroprotective effect against apoptotic stress and that this effect is dependent on the PI3-K/Akt pathway and inhibition of caspase-3 cleavage. This study provides evidence that Ang-1 is not just angiogenic but also neuroprotective. The understanding of neuroprotective mechanisms induced by Ang-1 may promote strategies based on the pleiotropic effects of angiogenic factors. Such approaches could be useful for the treatment of brain diseases in which both neuronal death and angiogenesis are involved.
Transforming growth factor alpha-induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity.
Gabriel C, Ali C, Lesné S, Fernández-Monreal M, Docagne F, Plawinski L, MacKenzie ET, Buisson A, Vivien D
FASEB J 1530-6860
PMID : 12490542
KEYWORDS : Animals|Apoptosis|drug effects|Astrocytes|cytology|Dose-Response Relationship, Drug|Gene Expression Regulation|drug effects|Mitogen-Activated Protein Kinases|drug effects|N-Methylaspartate|pharmacology|Neurons|cytology|Phosphorylation|drug effects|Plasminogen Activator Inhibitor 1|genetics|RNA, Messenger|drug effects|Tissue Plasminogen Activator|drug effects|Transforming Growth Factor alpha|pharmacology
Show abstract [+]
Although transforming growth factor (TGF)-alpha, a member of the epidermal growth factor (EGF) family, has been shown to protect neurons against excitotoxic and ischemic brain injuries, its mechanism of action remains unknown. In the present study, we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF-alpha rescues neurons from N-methyl-D-aspartate (NMDA)-induced excitotoxic death, with the obligatory presence of astrocytes. Because neuronal tissue-type plasminogen activator (t-PA) release was shown to potentiate NMDA-induced excitotoxicity, we observed that TGF-alpha treatment reduced NMDA-induced increase of t-PA activity in mixed cultures of neurons and astrocytes. In addition, we showed that although TGF-alpha induces activation of the extracellular signal-regulated kinases (ERKs) in astrocytes, it failed to activate p42/p44 in neurons. Finally, we showed that TGF-alpha, by an ERK-dependent mechanism, stimulates the astrocytic expression of PAI-1, a t-PA inhibitor, which mediates the neuroprotective activity of TGF-alpha against NMDA-mediated excitotoxic neuronal death. Taken together, we indicate that TGF-alpha rescues neurons from NMDA-induced excitotoxicity in mixed cultures through inhibition of t-PA activity, involving PAI-1 overexpression by an ERK-dependent pathway in astrocytes.
2002
Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates neuroprotective activity of transforming growth factor-beta 1 against NMDA-induced necrosis.
Docagne F, Nicole O, Gabriel C, Fernández-Monreal M, Lesné S, Ali C, Plawinski L, Carmeliet P, MacKenzie ET, Buisson A, Vivien D
Mol Cell Neurosci 1044-7431
PMID : 12504596
KEYWORDS : Animals|Animals, Newborn|Astrocytes|drug effects|Brain|drug effects|Calcium Signaling|drug effects|Cells, Cultured|Coculture Techniques|DNA-Binding Proteins|drug effects|Dose-Response Relationship, Drug|Excitatory Amino Acid Antagonists|pharmacology|Fetus|Mice|N-Methylaspartate|antagonists & inhibitors|Nerve Degeneration|chemically induced|Neurons|drug effects|Neuroprotective Agents|metabolism|Neurotoxins|antagonists & inhibitors|Plasminogen Activator Inhibitor 1|genetics|Recombinant Fusion Proteins|Smad3 Protein|Stroke|drug therapy|Tissue Plasminogen Activator|antagonists & inhibitors|Trans-Activators|drug effects|Transforming Growth Factor beta|metabolism|Transforming Growth Factor beta1
Show abstract [+]
The intravenous injection of the serine protease, tissue-type plasminogen activator (t-PA), has shown to benefit stroke patients by promoting early reperfusion. However, it has recently been suggested that t-PA activity, in the cerebral parenchyma, may also potentiate excitotoxic neuronal death. The present study has dealt with the role of the t-PA inhibitor, PAI-1, in the neuroprotective activity of the cytokine TGF-beta1 and focused on the transduction pathway involved in this effect. We demonstrated that PAI-1, produced by astrocytes, mediates the neuroprotective activity of TGF-beta 1 against N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. This t-PA inhibitor, PAI-1, protected neurons against NMDA-induced neuronal death by modulating the NMDA-evoked calcium influx. Finally, we showed that the activation of the Smad3-dependent transduction pathway mediates the TGF-beta-induced up-regulation of PAI-1 and subsequent neuroprotection. Overall, this study underlines the critical role of the t-PA/PAI-1 axis in the regulation of glutamatergic neurotransmission.
Matching gene expression with hypometabolism after cerebral ischemia in the nonhuman primate.
Chuquet J, Benchenane K, Liot G, Fernández-Monreal M, Toutain J, Blanchet S, Eveno E, Auffray C, Piétu G, Buisson A, Touzani O, MacKenzie ET, Vivien D
J Cereb Blood Flow Metab 0271-678X
PMID : 12368653
KEYWORDS : Animals|Brain|blood supply|Brain Ischemia|genetics|Cerebral Arteries|metabolism|Cloning, Molecular|Cluster Analysis|DNA, Complementary|Disease Models, Animal|Gene Expression Regulation|Male|Oligonucleotide Array Sequence Analysis|Oxygen Consumption|Papio
Show abstract [+]
To correlate brain metabolic status with the molecular events during cerebral ischemia, a cDNA array was performed after positron emission tomography scanning in a model of focal cerebral ischemia in baboons. Cluster analysis for the expression of 74 genes allowed the identification of 4 groups of genes. In each of the distinct groups, the authors observed a marked inflection in the pattern of gene expression when the CMRo was reduced by 48% to 66%. These patterns of coordinated modifications in gene expression could define molecular checkpoints for the development of an ischemic infarct and a molecular definition of the penumbra.
Transforming growth factor-beta1-modulated cerebral gene expression.
Lesné S, Blanchet S, Docagne F, Liot G, Plawinski L, MacKenzie ET, Auffray C, Buisson A, Piétu G, Vivien D
J Cereb Blood Flow Metab 0271-678X
PMID : 12218417
KEYWORDS : Animals|Animals, Newborn|Astrocytes|metabolism|Base Sequence|Cells, Cultured|Cerebral Cortex|metabolism|DNA Primers|Gene Expression Regulation|physiology|Glial Fibrillary Acidic Protein|genetics|Humans|Mice|Mice, Transgenic|Nerve Tissue Proteins|genetics|Neurons|metabolism|Oligonucleotide Array Sequence Analysis|Promoter Regions, Genetic|RNA, Messenger|genetics|Transcription, Genetic|Transforming Growth Factor beta|physiology|Transforming Growth Factor beta1
Show abstract [+]
Transforming growth factor-beta1 (TGF-beta1) plays a central role in the response of the brain to different types of injury. Increased TGF-beta1 has been found in the central nervous system of patients with acute or chronic disorders such as stroke or Alzheimer disease. To further define the molecular targets of TGF-beta1 in cerebral tissues, a selection of high-density cDNA arrays was used to characterize the mRNA expression profile of 7,000 genes in transgenic mice overexpressing TGF-beta1 from astrocytes as compared with the wild-type line. Selected findings were further evaluated by reverse transcription-polymerase chain reactions from independent transgenic and wild-type mice. Furthermore, the expression pattern of seven selected genes such as Delta-1, CRADD, PRSC-1, PAI-1, Apo-1/Fas, CTS-B, and TbetaR-II were confirmed in either cultured cortical neurons or astrocytes following TGF-beta1 treatment. The authors' observations enlarge the repertoire of known TGF-beta1-modulated genes and their possible involvement in neurodegenerative processes.
2001
A soluble transforming growth factor-beta (TGF-beta ) type I receptor mimics TGF-beta responses.
Docagne F, Colloc'h N, Bougueret V, Page M, Paput J, Tripier M, Dutartre P, MacKenzie ET, Buisson A, Komesli S, Vivien D
J Biol Chem 0021-9258
PMID : 11544249
KEYWORDS : Amino Acid Sequence|Animals|Base Sequence|Cell Division|physiology|Cell Line|Cricetinae|DNA Primers|Immunoglobulin G|metabolism|Mink|Molecular Sequence Data|Protein Conformation|Receptors, Transforming Growth Factor beta|chemistry|Sequence Homology, Amino Acid|Signal Transduction|Solubility|Transforming Growth Factor beta|metabolism
Show abstract [+]
Transforming growth factor-beta (TGF-beta) signaling requires a ligand-dependent interaction of TGF-beta receptors Tau beta R-I and Tau beta R-II. It has been previously demonstrated that a soluble TGF-beta type II receptor could be used as a TGF-beta antagonist. Here we have generated and investigated the biochemical and signaling properties of a soluble TGF-beta type I receptor (Tau beta RIs-Fc). As reported for the wild-type receptor, the soluble Tau beta R-I does not bind TGF-beta 1 on its own. Surprisingly, in the absence of TGF-beta1, the Tau beta RIs-Fc mimicked TGF-beta 1-induced transcriptional and growth responses in mink lung epithelial cells (Mv1Lu). Signaling induced by the soluble TGF-beta type I receptor is mediated via the obligatory presence of both TGF-beta type I and type II receptors at the cell surface since no signal was observed in Mv1Lu-derivated mutants for TGF-beta receptors R-1B and DR-26. The comparison between the structures of TGF-betas and a three-dimensional model of the extracellular domain of Tau beta RI has shown that five residues of the supposed binding site of TGF-beta 1 (Lys(31), His(34), Glu(5), Tyr(91), and Lys(94)) were found with equivalent biochemical properties and similar spatial positions.
Increased expression of transforming growth factor-beta after cerebral ischemia in the baboon: an endogenous marker of neuronal stress?
Ali C, Docagne F, Nicole O, Lesné S, Toutain J, Young A, Chazalviel L, Divoux D, Caly M, Cabal P, Derlon JM, MacKenzie ET, Buisson A, Vivien D
J Cereb Blood Flow Metab 0271-678X
PMID : 11435794
KEYWORDS : Animals|Biomarkers|Brain|metabolism|Brain Ischemia|etiology|Gene Expression|Magnetic Resonance Imaging|Male|Middle Cerebral Artery|surgery|Neurons|physiology|Oxygen Consumption|Papio|RNA, Messenger|analysis|Reverse Transcriptase Polymerase Chain Reaction|Tomography, Emission-Computed|Transforming Growth Factor beta|genetics
Show abstract [+]
There has been an increasing interest in recent years in the evaluation of the neuronal and glial responses to ischemic insult. Some cytokines, including transforming growth factor-beta (TGF-beta), that are overexpressed after experimental stroke in rodents are thought to be implicated in the neuronal processes that lead to necrosis. Thus, such cytokines could predict tissue fate after stroke in humans, although data are currently sparse for gyrencephalic species. The current study addressed the expression pattern of TGF-beta1 in a nonhuman primate model of middle cerebral artery occlusion. Focal permanent ischemia was induced for 1 or 7 days in 6 baboons and the following investigations were undertaken: cerebral oxygen metabolism (CMRO2) positron emission tomography studies, magnetic resonance imaging, postmortem histology, and reverse transcription-polymerase chain reaction. The aim of the current study was to correlate the expression of TGF-beta1 to the underlying metabolic and histologic state of the threatened cerebral parenchyma. The authors evidenced increased TGF-beta1 mRNA levels (up to 25-fold) in those regions displaying a moderate (20% to 49%) reduction in CMRO2. The current findings suggest that the greatly enhanced expression of TGF-beta1 in the penumbral zones that surround tissue destined to infarction may represent a robust index of potentially salvageable brain. The current investigation, in the nonhuman primate, strengthens the authors' hypothesis, derived from rodent models, that TGF-beta1 may be involved in the physiopathology of human stroke.
Neuroprotection mediated by glial cell line-derived neurotrophic factor: involvement of a reduction of NMDA-induced calcium influx by the mitogen-activated protein kinase pathway.
Nicole O, Ali C, Docagne F, Plawinski L, MacKenzie ET, Vivien D, Buisson A
J Neurosci 1529-2401
PMID : 11312287
KEYWORDS : Animals|Apoptosis|drug effects|Astrocytes|cytology|Brain Ischemia|metabolism|Calcium|metabolism|Cerebral Cortex|cytology|Chelating Agents|Drosophila Proteins|Fluorescent Dyes|Glial Cell Line-Derived Neurotrophic Factor|Glial Cell Line-Derived Neurotrophic Factor Receptors|Glycosylphosphatidylinositols|metabolism|MAP Kinase Signaling System|drug effects|Membrane Proteins|metabolism|Mice|Mice, Inbred Strains|Mitogen-Activated Protein Kinases|metabolism|N-Methylaspartate|antagonists & inhibitors|Necrosis|Nerve Growth Factors|Nerve Tissue Proteins|genetics|Neurons|cytology|Neuroprotective Agents|metabolism|Oxidation-Reduction|drug effects|Phosphorylation|drug effects|Proto-Oncogene Proteins|genetics|Proto-Oncogene Proteins c-ret|RNA, Messenger|metabolism|Receptor Protein-Tyrosine Kinases|genetics
Show abstract [+]
The glial cell line-derived neurotrophic factor (GDNF) is first characterized for its trophic activity on dopaminergic neurons. Recent data suggested that GDNF could modulate the neuronal death induced by ischemia. The purpose of this study was to characterize the influence of GDNF on cultured cortical neurons subjected to two paradigms of injury (necrosis and apoptosis) that have been identified during cerebral ischemia and to determine the molecular mechanisms involved. First, we demonstrated that both neurons and astrocytes express the mRNA and the protein for GDNF and its receptor complex (GFRalpha-1 and c-Ret). Next, we showed that the application of recombinant human GDNF to cortical neurons and astrocytes induces the activation of the MAP kinase (MAPK) pathway, as visualized by an increase in the phosphorylated forms of extracellular signal-regulated kinases (ERKs). Thereafter, we demonstrated that GDNF fails to prevent apoptotic neuronal death but selectively attenuates slowly triggered NMDA-induced excitotoxic neuronal death via a direct effect on cortical neurons. To further characterize the neuroprotective mechanisms of GDNF against NMDA-mediated neuronal death, we showed that a pretreatment with GDNF reduces NMDA-induced calcium influx. This effect likely results from a reduction of NMDA receptor activity rather than an enhanced buffering or extrusion capacity for calcium. Finally, we also demonstrated that an ERKs activation pathway is necessary for GDNF-mediated reduction of the NMDA-induced calcium response. Together, these results describe a novel mechanism by which the activation of MAPK induced by GDNF modulates NMDA receptor activity, a mechanism that could be responsible for the neuroprotective effect of GDNF in acute brain injury.
The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling.
Nicole O, Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, Vivien D, Buisson A
Nat Med 1078-8956
PMID : 11135617
KEYWORDS : Animals|Calcium|metabolism|Cell Death|Hydrolysis|Ion Transport|Membrane Potentials|Neurons|metabolism|Receptors, N-Methyl-D-Aspartate|metabolism|Signal Transduction|Tissue Plasminogen Activator|metabolism
Show abstract [+]
Tissue-plasminogen activator (t-PA) is now available for the treatment of thrombo-embolic stroke but adverse effects have been reported in some patients, particularly hemorrhaging. In contrast, the results of animal studies have indicated that t-PA could increase neuronal damage after focal cerebral ischemia. Here we report for the first time that t-PA potentiates signaling mediated by glutamatergic receptors by modifying the properties of the N-methyl-D-aspartate (NMDA) receptor. When depolarized, cortical neurons release bio-active t-PA that interacts with and cleaves the NR1 subunit of the NMDA receptor. Moreover, the treatment with recombinant t-PA leads to a 37% increase in NMDA-stimulated fura-2 fluorescence, which may reflect an increased NMDA-receptor function. These results were confirmed in vivo by the intrastriatal injection of recombinant-PA, which potentiated the excitotoxic lesions induced by NMDA. These data provide insight into the regulation of NMDA-receptor-mediated signaling and could initiate therapeutic strategies to improve the efficacy of t-PA treatment in man.
2000
Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain.
Ali C, Nicole O, Docagne F, Lesne S, MacKenzie ET, Nouvelot A, Buisson A, Vivien D
J Cereb Blood Flow Metab 0271-678X
PMID : 10894179
KEYWORDS : Animals|Apoptosis|drug effects|Astrocytes|cytology|Brain Chemistry|drug effects|Cells, Cultured|Cerebral Cortex|blood supply|Excitatory Amino Acid Agonists|pharmacology|Gene Expression|drug effects|Infarction, Middle Cerebral Artery|immunology|Interleukin-6|genetics|Ionomycin|pharmacology|Ionophores|pharmacology|Ischemic Attack, Transient|immunology|Male|N-Methylaspartate|pharmacology|Neurons|chemistry|Neuroprotective Agents|immunology|Neurotoxins|pharmacology|Polymerase Chain Reaction|RNA, Messenger|analysis|Rats|Rats, Sprague-Dawley|Receptors, AMPA|physiology|Receptors, Interleukin-6|genetics|Receptors, Kainic Acid|physiology|Receptors, N-Methyl-D-Aspartate|physiology|Transcription, Genetic|immunology
Show abstract [+]
In the brain, the expression of the pleiotropic cytokine interleukin-6 (IL-6) is enhanced in various chronic or acute central nervous system disorders. However, the significance of IL-6 production in such neuropathologic states remains controversial. The present study investigated the role of IL-6 after cerebral ischemia. First, the authors showed that focal cerebral ischemia in rats early up-regulated the expression of IL-6 mRNA, without affecting the transcription of its receptors (IL-6Ralpha and gp130). Similarly, the striatal injection of N-methyl-D-aspartate (NMDA) in rats, a paradigm of excitotoxic injury, activated the expression of IL-6 mRNA. The involvement of glutamatergic receptor activation was further investigated by incubating cortical neurons with NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). NMDA and ionomycin (a calcium ionophore) up-regulated IL-6 mRNA, suggesting that neurons may produce IL-6 in response to the calcium influx mediated through NMDA receptors. The potential role of IL-6 during ischemic/excitotoxic insults was then studied by testing the effect of IL-6 against apoptotic or excitotoxic challenges in cortical cultures. IL-6 did not prevent serum deprivation- or staurosporine-induced apoptotic neuronal death, or AMPA/kainate-mediated excitotoxicity. However, in both mixed and pure neuronal cultures, IL-6 dose-dependently protected neurons against NMDA toxicity. This effect was blocked by a competitive inhibitor of IL-6. Overall, the results suggest that the up-regulation of IL-6 induced by cerebral ischemia could represent an endogenous neuroprotective mechanism against NMDA receptor-mediated injury.
Serine protease inhibitors: novel therapeutic targets for stroke?
Vivien D, Buisson A
J Cereb Blood Flow Metab 0271-678X
PMID : 10826525
KEYWORDS : Animals|Cytokines|physiology|Humans|Neurodegenerative Diseases|physiopathology|Serine Endopeptidases|physiology|Serine Proteinase Inhibitors|physiology|Stroke|drug therapy
Show abstract [+]
Although the thrombolytic activity of tissue-type plasminogen activator (t-PA) may be beneficial in the acute treatment of stroke, recent studies have suggested that this serine protease could also play a critical role in determining the extent of neuronal death after injury to the central nervous system (CNS). This hypothesis is based on several experimental results: t-PA-deficient mice are resistant to excitotoxic neuronal death induced by the intrahippocampal injection of kainate; the infarct volume induced by occlusion of the middle cerebral artery is reduced in t-PA knockout mice; and the intravenous injection of t-PA can under certain circumstances potentiate the infarct volume in animals subjected to middle cerebral artery occlusion. In the CNS, the serine proteases have been identified to occur both in neurons and glial cells. Their enzymatic activity regulates the balance between the accumulation and the degradation of the extracellular matrix. They are involved in many physiologic functions, ranging from synaptic outgrowth during perinatal development to plasticity in adults. For instance, thrombin and t-PA are known to modulate neurite outgrowth and tissue remodeling in the early stages of development. In the adult brain, t-PA may contribute to the late phase of long-term potentiation and to the subsequent synaptic growth in the hippocampal mossy fiber pathway. This balance between the degradation and accumulation of the extracellular matrix may also be integral to various pathologic processes involved in acute brain injury. For example, compounds that modulate the activity of serine proteases exhibit neuroprotective activity. Based on the above, numerous studies have focused on the production and modulation of the endogenously produced serine protease inhibitors, termed serpins, such as type 1 plasminogen activator inhibitor, neuroserpin, and protease nexin-1. In the present review, we will discuss the need to distinguish between the potentially neurotoxic effects of t-PA and its beneficial effect on reperfusion. We will present data supporting the idea that the modulation of serine protease activity may represent a novel and efficient strategy for the treatment of acute cerebral injury in humans.
Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain.
Bernaudin M, Bellail A, Marti HH, Yvon A, Vivien D, Duchatelle I, Mackenzie ET, Petit E
Glia 0894-1491
PMID : 10756076
KEYWORDS : Animals|Astrocytes|metabolism|Brain|metabolism|Cells, Cultured|Erythropoietin|genetics|Hypoxia|genetics|Male|Mice|Mice, Inbred Strains|Neurons|metabolism|Oxidation-Reduction|Oxygen|metabolism|Polymerase Chain Reaction|RNA, Messenger|metabolism|Time Factors
Show abstract [+]
Erythropoietin (Epo), the major hormone controlling the hypoxia-induced increase in the number of erythrocytes, has also a functional role in the brain. However, few data exist as to the cellular source of brain-derived Epo as well as to the molecular mechanisms that control Epo expression in the central nervous system. Using patch-clamp and RT-PCR methods, we provide direct evidence that, besides astrocytes, neurons are a source of Epo in the brain. Both the astrocytic and neuronal expression of Epo mRNA are induced not only by hypoxia, but also by desferrioxamine (DFX) and cobalt chloride (CoCl(2)), two agents known to mimic the hypoxic induction of Epo in hepatoma cells. This induction is blocked by cycloheximide suggesting that de novo protein synthesis is required. Furthermore, the addition of H(2)O(2) decreases the hypoxia-induced Epo mRNA levels. These data indicate that, following hypoxia, a common oxygen sensing and signaling pathway leads to increased Epo gene expression in both nervous and hepatoma cells; this pathway would be dependent on the redox-state of the brain. Furthermore, we show that the in vivo administration of CoCl(2) and DFX to mice induces an increased Epo mRNA level in the neocortex. As Epo protects the brain against ischemia, our in vivo experiments suggest that the use of molecules such as CoCl(2) or DFX, that provoke an increased Epo gene expression in the brain, could be useful in the development of potential therapeutic strategies for the treatment of hypoxic or ischemic brain injury.
1999
A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury.
Ruocco A, Nicole O, Docagne F, Ali C, Chazalviel L, Komesli S, Yablonsky F, Roussel S, MacKenzie ET, Vivien D, Buisson A
J Cereb Blood Flow Metab 0271-678X
PMID : 10598939
KEYWORDS : Animals|Cell Death|drug effects|Cells, Cultured|Cerebral Cortex|cytology|Cerebral Infarction|pathology|Fetus|Gene Expression Regulation|drug effects|Humans|Immunoglobulin Fc Fragments|Ischemic Attack, Transient|pathology|Male|Mice|Middle Cerebral Artery|N-Methylaspartate|toxicity|Neurons|cytology|Neuroprotective Agents|Protein Serine-Threonine Kinases|Rats|Rats, Sprague-Dawley|Receptor, Transforming Growth Factor-beta Type II|Receptors, Transforming Growth Factor beta|genetics|Recombinant Fusion Proteins|pharmacology|Reverse Transcriptase Polymerase Chain Reaction|Transforming Growth Factor beta|antagonists & inhibitors
Show abstract [+]
Various studies describe increased concentrations of transforming growth factor-beta (TGF-beta) in brain tissue after acute brain injury. However, the role of endogenously produced TGF-beta after brain damage to the CNS remains to be clearly established. Here, the authors examine the influence of TGF-beta produced after an episode of cerebral ischemia by injecting a soluble TGF-beta type II receptor fused with the Fc region of a human immunoglobulin (TbetaRIIs-Fc). First, this molecular construct was characterized as a selective antagonist of TGF-beta. Then, the authors tested its ability to reverse the effect of TGF-beta1 on excitotoxic cell death in murine cortical cell cultures. The addition of 1 microg/mL of TbetaRIIs-Fc to the exposure medium antagonized the neuroprotective activity of TGF-beta1 in N-methyl-D-aspartate (NMDA)-induced excitotoxic cell death. These results are consistent with the hypothesis that TGF-beta1 exerts a negative modulatory action on NMDA receptor-mediated excitotoxicity. To determine the role of TGF-beta1 produced in response to brain damage, the authors used a model of an excitotoxic lesion induced by the intrastriatal injection of 75 nmol of NMDA in the presence of 1.5 microg of TbetaRIIs-Fc. The intrastriatal injection of NMDA was demonstrated to induce an early upregulation of the expression of TGF-beta1 mRNA. Furthermore, when added to the excitotoxin, TbetaRIIs-Fc increased (by 2.2-fold, P < 0.05) the lesion size. These observations were strengthened by the fact that an intracortical injection of TbetaRIIs-Fc in rats subjected to a 30-minute reversible cerebral focal ischemia aggravated the volume of infarction. In the group injected with the TGF-beta1 antagonist, a 3.5-fold increase was measured in the infarction size (43.3 +/- 9.5 versus 152.8 +/- 46.3 mm3; P < 0.05). In conclusion, by antagonizing the influence of TGF-beta in brain tissue subjected to excitotoxic or ischemic lesion, the authors markedly exacerbated the resulting extent of necrosis. These results suggest that, in response to such insults, brain tissue responds by the synthesis of a neuroprotective cytokine, TGF-beta1, which is involved in the limitation of the extent of the injury. The pharmacologic potentiation of this endogenous defensive mechanism might represent an alternative and novel strategy for the therapy of hypoxic-ischemic cerebral injury.
Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia.
Docagne F, Nicole O, Marti HH, MacKenzie ET, Buisson A, Vivien D
FASEB J 0892-6638
PMID : 10428756
KEYWORDS : Amyloid beta-Protein Precursor|Animals|Astrocytes|metabolism|Brain Ischemia|genetics|Carrier Proteins|genetics|Cell Death|genetics|Cells, Cultured|Gene Expression Regulation|Mice|Neurons|pathology|Neuropeptides|genetics|Plasminogen Activator Inhibitor 1|genetics|Protease Nexins|Receptors, Cell Surface|Serpins|genetics|Tissue Plasminogen Activator|genetics|Transforming Growth Factor beta|genetics|Neuroserpin
Show abstract [+]
The tissue type plasminogen activator (t-PA) is a serine protease that is involved in neuronal plasticity and cell death induced by excitotoxins and ischemia in the brain. t-PA activity in the central nervous system is regulated through the activation of serine protease inhibitors (serpins) such as the plasminogen activator inhibitor (PAI-1), the protease nexin-1 (PN-1), and neuroserpin (NSP). Recently we demonstrated in vitro that PAI-1 produced by astrocytes mediates the neuroprotective effect of the transforming growth factor-beta1 (TGF-beta1) in NMDA-induced neuronal cell death. To investigate whether serpins may be involved in neuronal cell death after cerebral ischemia, we determined, by using semiquantitative RT-PCR and in situ hybridization, that focal cerebral ischemia in mice induced a dramatic overexpression of PAI-1 without any effect on PN-1, NSP, or t-PA. Then we showed that although the expression of PAI-1 is restricted to astrocytes, PN-1, NSP, and t-PA are expressed in both neurons and astrocytes. Moreover, by using semiquantitative RT-PCR and Western blotting, we observed that only the expression of PAI-1 was modulated by TGF-beta1 treatment via a TGF-beta-inducible element contained in the PAI-1 promoter (CAGA box). Finally, we compared the specificity of TGF-beta1 action with other members of the TGF-beta family by using luciferase reporter genes. These data show that TGF-beta and activin were able to induce the overexpression of PAI-1 in astrocytes, but that bone morphogenetic proteins, glial cell line-derived neutrophic factor, and neurturin did not. These results provide new insights into the regulation of the serpins/t-PA axis and the mechanism by which TGF-beta may be neuroprotective.
1998
Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor beta1.
Buisson A, Nicole O, Docagne F, Sartelet H, Mackenzie ET, Vivien D
FASEB J 0892-6638
PMID : 9837858
KEYWORDS : Animals|Astrocytes|drug effects|Cell Death|drug effects|Mice|N-Methylaspartate|pharmacology|Neuroglia|cytology|Neurons|cytology|Neuroprotective Agents|pharmacology|Plasminogen Activator Inhibitor 1|metabolism|Receptors, Transforming Growth Factor beta|genetics|Serine Proteinase Inhibitors|biosynthesis|Tissue Plasminogen Activator|metabolism|Transforming Growth Factor beta|pharmacology|Up-Regulation
Show abstract [+]
Serine proteases play a key role in the fundamental biology of the central nervous system (CNS), and recent data suggest their involvement in the pathophysiology of neurodegenerative diseases. Little is known about the physiological regulation of these proteases in the CNS. Among the multiple growth factors present in the brain, transforming growth factor beta1 (TGF-beta1) has been described as an injury-related growth factor. However, its beneficial or deleterious role remains unclear. In the present study, we investigated the influence of TGF-beta1 in apoptosis and necrosis, two mechanisms involved in ischemic neuronal death. We show that TGF-beta1 exerts a neuroprotective role restricted to necrosis induced by N-methyl-D-aspartate. This effect is observable only in the obligatory presence of TGF-beta1-responsive astrocytes. We demonstrate that this neuroprotective activity is mediated through an up-regulation of a serine protease inhibitor (PAI-1) in astrocytes. These results underline the involvement of serine proteases and extracellular matrix components such as the PAI-1/t-PA axis in the excitotoxic cascade. Moreover, regardless of the underlying mechanisms of t-PA involvement in excitotoxic injury, our observations might warn against the use of tissular plasminogen activator as an alternative therapy for the treatment of hypoxic-ischemic injury in the brain.
Evidence of type I and type II transforming growth factor-beta receptors in central nervous tissues: changes induced by focal cerebral ischemia.
Vivien D, Bernaudin M, Buisson A, Divoux D, MacKenzie ET, Nouvelot A
J Neurochem 0022-3042
PMID : 9603194
KEYWORDS : Activin Receptors, Type I|Animals|Animals, Newborn|Arterial Occlusive Diseases|complications|Astrocytes|cytology|Cells, Cultured|Cerebral Arterial Diseases|complications|Cerebral Cortex|metabolism|Epithelial Cells|metabolism|Humans|Immunohistochemistry|Ischemic Attack, Transient|etiology|Mice|Mink|Neurons|cytology|Polymerase Chain Reaction|Protein Serine-Threonine Kinases|biosynthesis|RNA, Messenger|biosynthesis|Receptor, Transforming Growth Factor-beta Type I|Receptor, Transforming Growth Factor-beta Type II|Receptors, Transforming Growth Factor beta|biosynthesis
Show abstract [+]
The peptides of the transforming growth factor-beta (TGF-beta) family transduce their signal through ligand-induced heteromeric complexes that consist of type I and type II serine/threonine kinases. Both TGF-beta receptors are abundant in many peripheral tissues, but clear evidence of their expression in cortical astrocytes and neurons has not been published so far. In this study, we investigated the expression of type I and type II TGF-beta receptors and their potential ligands (TGF-beta1, TGF-beta2, and TGF-beta3) in the CNS by using RT-PCR and immunohistochemistry. Moreover, to further the study of those cell types that exhibit TGF-beta isoforms and related receptors, we examined through the use of RT-PCR whether cortical neurons and astrocytes in culture express the mRNAs for TGF-betas and their receptors. We show that the three TGF-beta isoform mRNAs are present in the CNS. However, although astrocytes in culture display all three isoforms, neurons in culture express only TGF-beta2. We have demonstrated that both type I and type II TGF-beta receptor mRNAs and proteins are present in the CNS and in cultures of cortical neurons and astrocytes. Thus, TGF-betas may act as autocrine and paracrine signals in the CNS between both neurons and astrocytes via the same receptor systems as those found in peripheral tissues. TGF-beta1 has been shown to be induced following hypoxic-ischemic brain injury and may play a critical role in the pathophysiology of degenerative processes in the CNS. In the present investigation, we confirmed that the expression of TGF-beta1 was increased markedly up until 24 h and thereafter was stable over the first 3 days following permanent occlusion of the middle cerebral artery in mice. However, whereas the expression of the type I TGF-beta receptor was not altered by the ischemic insult, the pattern of the type II TGF-beta receptors was modified dramatically in the ischemic area 3 days after the occlusion. These data show that, even if ligands are present, they may not be able to transduce their signal. Finally, the present study clearly demonstrates that a knowledge of the expression of ligand-specific receptors following brain injury is a fundamental step in clarifying the involvement of cytokines in neurodegenerative diseases.
1996
An inositolphosphate glycan released by TGF-beta mimics the proliferative but not the transcriptional effects of the factor and requires functional receptors.
Bogdanowicz P, Vivien D, Felisaz N, Léon V, Pujol JP
Cell Signal 0898-6568
PMID : 9023015
KEYWORDS : Animals|Cartilage, Articular|cytology|Cell Division|Cell Line|Cells, Cultured|DNA|biosynthesis|Gene Expression Regulation|Genes, Reporter|Inositol Phosphates|metabolism|Mink|Molecular Mimicry|Polysaccharides|metabolism|Rabbits|Receptors, Transforming Growth Factor beta|metabolism|Signal Transduction|Transcription, Genetic|Transforming Growth Factor beta|pharmacology
Show abstract [+]
Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional polypeptide that regulates a number of cellular processes including cell growth and deposition of extracellular matrix protein. Despite the fact that the signal transduction by TGF-beta has been intensively studied, the molecular mechanisms of that pathway are not clear. We have studied the possibility that an inositolphosphate glycan (IPG) is involved in transmission of the TGF-beta 1 signal. We show that TGF-beta 1 induces IPG release in both rabbit articular chondrocytes (RAC), which are growth stimulated by the factor and Mv1Lu cell line, which is growth inhibited. This release requires functional TGF-beta heteromeric receptors in these two cell types. We also demonstrate that IPG mimics TGF-beta 1-induced growth stimulation in mesenchymal cells (+100%) and growth inhibition in epithelial cells (-80%). Moreover TGF-beta receptor I (T beta R-I) is not required for inhibition of proliferation induced by IPG since derivated mutants of the Mv1Lu cell line lacking T beta R-I intracellular domain (R-1B) are significantly inhibited (-65%). Additionally, we show that IPG does not take part in the signalling pathway that leads to activation of matrix gene transcription. These results suggest that TGF-beta effects on growth regulation and extracellular matrix synthesis implicate two different signalling pathways, IPG being only involved in growth regulation.
[Physiopathology of arthrotic cartilage].
Pujol JP, Galéra P, Vivien D, Redini F, Boumediene K
Rev Prat 0035-2640
PMID : 8978150
KEYWORDS : Animals|Cartilage, Articular|metabolism|Humans|Osteoarthritis|metabolism|Rabbits|Receptors, Transforming Growth Factor beta|genetics|Transforming Growth Factor beta|genetics
1995
Modulation of rabbit articular chondrocyte (RAC) proliferation by TGF-beta isoforms.
Boumediene K, Vivien D, Macro M, Bogdanowicz P, Lebrun E, Pujol JP
Cell Prolif 0960-7722
PMID : 7772639
KEYWORDS : Animals|Cartilage, Articular|cytology|Cell Count|Cell Cycle|drug effects|Cell Division|drug effects|Cells, Cultured|Flow Cytometry|Rabbits|Thymidine|Transforming Growth Factor beta|biosynthesis|Tritium
Show abstract [+]
We have previously shown that TGF-beta 1 exerts a bifunctional effect on RAC proliferation. Added to quiescent cultures, it inhibits the entry of G0/G1 cells into S phase whereas in S phase synchronized populations, it stimulates the DNA replication rate with a delayed G2 + M phase and a subsequent transient increase of cell number. As TGF-beta 2 and beta 3 isoforms are also expressed in bone and cartilage tissues, it was of interest to study their effect on RAC proliferation, in comparison to that of TGF-beta 1. Using cell counting and tritiated thymidine incorporation, we found that all the TGF-beta s used here induced an increase of RAC proliferation rate occurring between 24 and 48 h of exposure. TGF-beta 2 appeared as the most efficient form as judged from the maximum of thymidine labelling. However, TGF-beta 3 induced an increase of cell number slightly higher than both TGF-beta 1 and TGF-beta 2 (+30% versus 20% for TGF-beta 1 and beta 2). TGF-beta 2 and beta 3 were able to stimulate the DNA replication rate as previously demonstrated for TGF-beta 1. However, the effect occurred later for TGF-beta 2 and beta 3 (12 h) than for TGF-beta 1 (6 h). This was confirmed by flow cytometric analysis of DNA content. In addition, immunodetection by flow cytometry demonstrated that all TGF-beta isoforms enhanced endogenous expression of TGF-beta-related peptides. The effect was shown to be associated with the cell cycle S phase and was greater for TGF-beta 3 than for TGF-beta 1 and beta 2. These findings suggest that TGF-beta s could act on RAC functions via autocrine and paracrine ways. Taken together, these data indicate that TGF-beta s may modulate proliferation of articular chondrocytes and therefore could play a role in the activation of these cells in the early stages of osteoarthritis.
Ligand-induced recruitment and phosphorylation of reduced TGF-beta type I receptor.
Vivien D, Wrana JL
Exp Cell Res 0014-4827
PMID : 7589256
KEYWORDS : Animals|Cell Line|metabolism|Dithiothreitol|pharmacology|Epithelial Cells|Epithelium|ultrastructure|Ligands|Mink|Phosphorylation|Receptors, Transforming Growth Factor beta|metabolism|Signal Transduction|physiology
Show abstract [+]
Receptors I (T beta R-I) and II (T beta R-II) of transforming growth factor-beta (TGF-beta) are components of a heteromeric complex in which receptor I requires receptor II to bind ligand, and receptor II requires receptor I to signal. We show that pretreatment of cells with low concentrations of dithiothreitol, which is known to disrupt ligand binding to T beta R-I, does not prevent interaction and complex formation between T beta R-II and T beta R-I. Nevertheless, our results demonstrate that ligand interaction with T beta R-I is able to induce high-affinity convertion to the complex formed. We also demonstrate that transphosphorylation of T beta R-I through bound T beta R-II can occur independently of ligand binding to T beta R-I.
1994
Different phosphorylated forms of inositolphosphate glycan could be involved in the transforming growth factor-beta 1 (TGF-beta 1) signalling pathway.
Vivien D, Bogdanowicz P, Boumediene K, Martiny L, Haye B, Pujol JP
Cell Signal 0898-6568
PMID : 8086280
KEYWORDS : Animals|Cartilage, Articular|cytology|Cell Cycle|Cell Division|Cells, Cultured|Chromatography, Ion Exchange|DNA Replication|drug effects|Glucosamine|metabolism|Glycosylphosphatidylinositols|metabolism|Humans|Inositol Phosphates|metabolism|Phosphorylation|Polysaccharides|metabolism|Protein Kinases|metabolism|Rabbits|Signal Transduction|Transforming Growth Factor beta|metabolism
Show abstract [+]
Labelling with [3H]glucosamine was used to prepare a transforming growth factor-beta 1 (TGF-beta 1)-sensitive glycosylphosphatidylinositol (GPI) from monolayer cultures of rabbit articular chondrocytes (RAC), which may be involved in control of the cell cycle. The polar headgroup of this glycosylphosphatidylinositol was generated by both phosphatidylinositol-specific phospholipase C (PI-PLC) and pronase E digestion. The molecule emerged in only one peak on a Dowex AG1-X8 chromatogram, eluted at 0.1 N ammonium formate. In contrast, similar experiments performed on cellular extract from cultures previously labelled with [3H]glucosamine displayed four radioactive peaks eluting at 0.1, 0.2, 0.5 and 1 N ammonium formate, respectively. Evidence that the eluting position of these peaks was dependent on the number of phosphate residues present in each fraction was demonstrated by both [32P]phosphorus labelling and change in the position of alkaline phosphatase-induced shift in elution volume. We also demonstrated that the GPI-derived inositolphosphate glycan (IPG) could be hyperphosphorylated into the cell under the action of a kinase whose activity was enhanced by TGF-beta 1 itself. We have also shown that all of these IPG forms could mimic the TGF-beta-induced increase of DNA replication rate of RAC, with a higher activity for peaks III and IV than peaks I and II.
Transforming growth factor-beta (TGF-beta) and articular chondrocytes.
Pujol JP, Galera P, Pronost S, Boumediene K, Vivien D, Macro M, Min W, Redini F, Penfornis H, Daireaux M
Ann Endocrinol (Paris) 0003-4266
PMID : 7802428
KEYWORDS : Animals|Cartilage, Articular|cytology|Cell Division|drug effects|Extracellular Matrix|metabolism|G2 Phase|Interleukin-1|antagonists & inhibitors|Rabbits|Receptors, Transforming Growth Factor beta|metabolism|Transforming Growth Factor beta|pharmacology
Show abstract [+]
Transforming growth factor-beta (TGF-beta) has a dual effect on the proliferation of joint chondrocytes. In medium with a low serum concentration, it inhibits cell growth, while in medium supplemented with 10% fetal calf serum it stimulates cell growth. This stimulation leads to a higher replication rate an a larger number of cells in the G2/M phase of the cell cycle. Since these cells have already replicated their DNA, they can begin mitosis when stimulated by a EGF type factor. This mechanism involves the systems of the TGF-beta receptors which appear to vary with the cell cycle. In addition, a glycane inositophosphate may play a role as a second messenger for TGG-beta in this action. Finally, TGF-beta cannot restore the chondrocyte phenotype in dedifferentiated cells nor limit the dedifferentiation process. It exerts a opposing effect to the deleterious effects of interleukin-1 by inhibiting the expression of the receptors of this cytokine at the level of transcription. These in vitro effects would suggest that TGF-beta plays an important role in the repair potentiality of joint cartilage especially in arthrosis. In vivo studies are however necessary to verify this hypothesis.
1993
Interleukin-1 and naproxen down-regulate the expression of IL-1 receptors in cultured human rheumatoid synovial cells (HRSC).
Pronost S, Delecoeuillerie G, Rédini F, Paolozzi L, Vivien D, Galéra P, Loyau G, Pujol JP
Agents Actions Suppl 0379-0363
PMID : 8456631
KEYWORDS : Arthritis, Rheumatoid|pathology|Down-Regulation|drug effects|Humans|Interleukin-1|metabolism|Iodine Radioisotopes|Kinetics|Naproxen|pharmacology|Receptors, Interleukin-1|drug effects|Recombinant Proteins|pharmacology|Synovial Membrane|pathology
Show abstract [+]
Using affinity binding of [125I]-IL-1 alpha and Scatchard analysis, we demonstrate here that exposure of cultured synovial cells (HRSC) to NPX (10(-4) M) for 96 h decreased the binding of IL-1 by 20 to 35%. This effect results from a down-regulation of the IL-1 receptors without change in the apparent binding affinity (kD: 770 pM). Pretreatment of cultures with IL-1 alpha (500 pg/ml) reduced the total binding of [125I]-IL-1 alpha on HRSC by 65%, indicating that IL-1 decreases the expression of its own receptors.
IPG (inositolphosphate glycan) as a cellular signal for TGF-beta 1 modulation of chondrocyte cell cycle.
Vivien D, Petitfrère E, Martiny L, Sartelet H, Galéra P, Haye B, Pujol JP
J Cell Physiol 0021-9541
PMID : 8388000
KEYWORDS : Animals|Cartilage, Articular|cytology|Cell Cycle|drug effects|Cell Division|Cells, Cultured|DNA Replication|drug effects|Glycosylphosphatidylinositols|physiology|Humans|Hydrolysis|Inositol Phosphates|metabolism|Phosphatidylinositol Diacylglycerol-Lyase|Phosphoinositide Phospholipase C|Phosphoric Diester Hydrolases|metabolism|Polysaccharides|metabolism|Rabbits|Receptors, Cell Surface|physiology|Receptors, Transforming Growth Factor beta|Signal Transduction|Transforming Growth Factor beta|pharmacology
Show abstract [+]
The knowledge of transforming growth factor (TGF)-beta receptors has greatly progressed in the recent years. TGF-beta receptors type I and II have been implicated in the modulation of cell proliferation, whereas type III (betaglycan) may act as a component presenting TGF-beta to its signaling receptors. In addition, four other proteins that bind TGF-beta 1 or TGF-beta 2 have been recently identified in some cell lines, three being anchored to the membrane through a glycosylphosphatidylinositol (GPI). Despite this knowledge, the molecular mechanism of signal transduction through the TGF-beta receptors remain an enigma. TGF-beta family does not signal via any of the classical pathways. As GPI anchors of membrane proteins have been implicated in the transduction of some hormonal effects, we investigated the putative role of GPI in signaling the TGF-beta effects on the proliferation of rabbit articular chondrocytes (RAC). We previously showed that TGF-beta 1 increased DNA replication rate of RAC, with a recruitment of cells in G2/M followed by a subsequent mitosis wave. Here, we find that the factor causes specific GPI hydrolysis, with correlated increase of inositolphosphate glycan (IPG). This effect was specifically inhibited by antibodies that bind TGF-beta 1. Using [3H]-inositol labeling and Triton X-114 extraction, we demonstrate that a hydrophobic material from the membrane is cleaved by treatment of cell cultures with phosphatidylinositol specific phospholipase C (PI-PLC) or by exposure to TGF-beta, supporting that a PI-anchored molecule gives rise to IPG by TGF-beta-induced hydrolysis. The biological relevance of this hydrolysis was demonstrated by the enhancing effect of purified IPG on the DNA synthesis rate, which mimicked the TGF-beta action. These results demonstrate that IPG could be an early messenger in the cellular signaling that mediates the effect of TGF-beta on RAC growth.
Human rheumatoid synovial cells (HRSC) in culture express TGF-beta receptors and are growth stimulated by the factor.
Pronost S, Rédini F, Vivien D, Galéra P, Pujol JP
Agents Actions Suppl 0379-0363
PMID : 8384400
KEYWORDS : Arthritis, Rheumatoid|metabolism|Autoradiography|Cell Division|drug effects|Cells, Cultured|Cross-Linking Reagents|pharmacology|Electrophoresis, Polyacrylamide Gel|Humans|Iodine Radioisotopes|Kinetics|Receptors, Cell Surface|biosynthesis|Receptors, Transforming Growth Factor beta|Stimulation, Chemical|Synovial Membrane|cytology|Transforming Growth Factor beta|pharmacology
Show abstract [+]
TGF-beta (5 ng/ml) increased the proliferation rate of HRSC by 30% after 96 h of treatment. One type of TGF-beta binding system, with apparent Kd of 953 pM and a number of 29,400 receptors/cell, was detected by Scatchard analysis of [125I]-TGF-beta binding. However, crosslinking experiments and SDS-PAGE separation showed five TGF-beta binding proteins: 50, 70, 110, 140 and 400 kDa. We may suggest that the affinities of these receptors are too close to be revealed by Scatchard plot. All together, the data suggest that TGF-beta plays a role in the hyperplasia of RA synovial tissue.
Rabbit articular chondrocytes (RAC) express distinct transforming growth factor-beta receptor phenotypes as a function of cell cycle phases.
Vivien D, Redini F, Galéra P, Lebrun E, Loyau G, Pujol JP
Exp Cell Res 0014-4827
PMID : 8384118
KEYWORDS : Animals|Binding Sites|Cartilage, Articular|metabolism|Cell Cycle|physiology|Cell Division|drug effects|Cells, Cultured|drug effects|Phenotype|Rabbits|Receptors, Cell Surface|physiology|Receptors, Transforming Growth Factor beta|Transforming Growth Factor beta|metabolism
Show abstract [+]
We previously showed that TGF-beta 1 exerted a bifunctional effect on the proliferation of cultured rabbit articular cells (RAC), depending on the serum level present in the medium. Slowly proliferating cells (2% fetal calf serum, FCS) were growth-inhibited by TGF-beta 1, whereas actively dividing cells (10% FCS) exhibited a transient growth increase in response to the factor. Here we demonstrate that both of these cycling populations of RAC display two distinct systems of high-affinity binding sites for TGF-beta 1. However, a significant increase (60%) in the number of the highest affinity receptors was observed in the 2% FCS-treated cells compared to those cultured in 10% FCS (in 2% FCS: Kd1 = 295 +/- 78 pM, 1899 +/- 99 sites/cell; Kd2 = 1106 +/- 61 pM, 9935 +/- 940 sites/cell; in 10% FCS:Kd1 = 287 +/- 10 pM, 1054 +/- 65 sites/cell; Kd2 = 1128 +/- 101 pM, 8257 +/- 61 sites/cell). This finding was correlated with the greater number of G0/G1 cells in the population cultured in 2% FCS (70%) compared to that exposed to 10% FCS (55%). The data was further confirmed using cells synchronized in late G1/early S phase (> 80% of S phase). This cell population exhibited a single class of TGF-beta 1 high-affinity binding sites (Kd = 1140 +/- 85 pM, 6836 +/- 1787 sites/cell). In contrast, cells synchronized in G0/G1 (> 80% of cells in G0/G1) expressed one binding system of Kd = 402 +/- 59 pM (940 +/- 56 sites/cell). These results clearly demonstrate that cultured RAC express different TGF-beta 1 receptor systems as a function of the cell cycle.
1992
Effect of transforming growth factor-beta 1 (TGF-beta 1) on matrix synthesis by monolayer cultures of rabbit articular chondrocytes during the dedifferentiation process.
Galéra P, Rédini F, Vivien D, Bonaventure J, Penfornis H, Loyau G, Pujol JP
Exp Cell Res 0014-4827
PMID : 1572404
KEYWORDS : Animals|Cartilage, Articular|metabolism|Cell Differentiation|drug effects|Cell Division|drug effects|Cells, Cultured|Collagen|biosynthesis|Extracellular Matrix|metabolism|Gene Expression|drug effects|Glycosaminoglycans|biosynthesis|In Vitro Techniques|Proteoglycans|metabolism|RNA, Messenger|genetics|Rabbits|Transforming Growth Factor beta|pharmacology
Show abstract [+]
Since transforming growth factor-beta (TGF-beta) has been shown earlier to induce the chondrocyte phenotype in embryonic rat mesenchymal cells with production of cartilage-specific type II collagen and proteoglycans, it was of interest to determine whether the factor could also influence the differentiation state of articular chondrocytes maintained in monolayer culture. Using rabbit articular chondrocytes (RAC) in primary and passaged cultures, we demonstrate that the loss of the phenotype accompanying the subculture was not significantly influenced by the presence of TGF-beta. The factor exerted an inhibitory effect on collagen synthesis in a 6-day exposure of primary cultures whereas it stimulated that production throughout the subsequent passages. Steady-state levels of mRNAs encoding type I, II, and III procollagens were correlated with the amounts of cognate proteins produced, suggesting that both inhibition and stimulation were exerted at a transcriptional level. The pattern of proteoglycans produced in primary culture, essentially chondroitin sulfate-containing molecules, was altered by the subculture-induced RAC dedifferentiation, as shown by decrease in chondroitin sulfate formation and progressive appearance of hyaluronic acid. Contrasting with its effect on collagen synthesis, TGF-beta did not significantly change the proteoglycan production of RAC in our conditions whenever it was added at the beginning of the primary cultures or in the subsequent passages. Altogether, our data indicate that the effect of TGF-beta on RAC collagen synthesis depends on whether they are fully differentiated. Moreover, the data show that the factor does not prevent the loss of RAC phenotype but rather contributes to the dedifferentiation process since it exerts differential effects on the major components of extracellular matrix, collagen, and proteoglycans.
Transforming growth factor-beta 1 (TGF-beta 1) up-regulation of collagen type II in primary cultures of rabbit articular chondrocytes (RAC) involves increased mRNA levels without affecting mRNA stability and procollagen processing.
Galéra P, Vivien D, Pronost S, Bonaventure J, Rédini F, Loyau G, Pujol JP
J Cell Physiol 0021-9541
PMID : 1447320
KEYWORDS : Animals|Ascorbic Acid|pharmacology|Cartilage, Articular|cytology|Cells, Cultured|Collagen|metabolism|Dinoprostone|biosynthesis|Drug Stability|Electrophoresis, Polyacrylamide Gel|Homeostasis|Indomethacin|pharmacology|Isomerism|Procollagen|classification|Protein Processing, Post-Translational|drug effects|RNA, Messenger|metabolism|Rabbits|Transforming Growth Factor beta|pharmacology
Show abstract [+]
The effect of transforming growth factor-beta 1 (TGF-beta 1) on collagen biosynthesis was investigated in confluent primary monolayer cultures of rabbit articular chondrocytes (RAC). Exposure to TGF-beta (0.1, 1, and 10 ng/ml) in serum-free medium caused a dose- and time-dependent stimulation of collagen biosynthesis associated with an increase of steady-state levels of procollagen type II mRNA. Elevation of the mRNA steady-state did not result from a stabilization of the transcript, as shown by measure of the mRNA half-life. Electrophoresis (SDS-PAGE) showed that TGF-beta stimulates the synthesis of most collagen isotypes, including type II, without qualitative change in their distribution. Moreover, pulse-chase experiments revealed that TGF-beta did not affect the processing rate of type II procollagen. TGF-beta slightly stimulated the production of prostaglandin E2 (PGE2), which could in turn exert an inhibition on collagen synthesis. However, addition of indomethacin to block prostaglandin synthesis did not further enhance the TGF-beta-induced stimulation of collagen production, suggesting that this mediator was not implicated in the effect. Moreover, TGF-beta increased steady-state levels of procollagen type II, I, and III mRNAs even in the presence of indomethacin. Despite these increased mRNA levels, only the production of type II collagen was significantly augmented, suggesting that type I procollagen mRNA was not fully translated. In addition, the TGF-beta-induced stimulation of collagen synthesis was observed whenever ascorbic acid is added or not in the culture medium. In conclusion, TGF-beta, which is present in great amount in bone and cartilage, can increase the collagen production of cultured RAC and might therefore play a role in the early events of cartilage repair, such as those observed in osteoarthritis.
Flow cytometric detection of transforming growth factor-beta expression in rabbit articular chondrocytes (RAC) in culture--association with S-phase traverse.
Vivien D, Boumedienne K, Galera P, Lebrun E, Pujol JP
Exp Cell Res 0014-4827
PMID : 1426052
KEYWORDS : Animals|Cartilage, Articular|cytology|Cell Cycle|Cell Division|Cells, Cultured|DNA|analysis|Flow Cytometry|methods|Rabbits|S Phase|physiology|Transforming Growth Factor beta|biosynthesis
Show abstract [+]
We have previously shown that TGF-beta 1 decreased the entry of G0/G1-synchronized rabbit articular chondrocytes (RAC) into S-phase, whereas it enhanced the proliferation rate of actively dividing cells (asynchronous or S-phase-synchronized cells). The growth proliferative effect was accompanied by both increased DNA replication rate and G2/M delay. Since TGF-beta mRNA has been detected in chondrocytes, it was of interest to study the expression of the factor in correlation with the cell cycle of RAC. Using cytofluorometric analysis of both DNA content and TGF-beta protein level, we demonstrated that S-phase-synchronized RAC constitutively expressed TGF-beta, whereas G0/G1-synchronized cells only display very low levels of the factor. The data showed that the expression of TGF-beta is correlated with S-phase traverse since it increases with the percentage of cells in S-phase (less than 27% in G0/G1 to 70% in S-phase-synchronized cells). Moreover, exposure of RAC to TGF-beta 1 (1 ng/ml) for 24 h increased the percentage of positive cells, independently of the number of cells in S-phase, indicating that the factor may up-regulate its own expression. All together, these data suggest that TGF-beta could play a role in initiating the proliferation of articular chondrocytes during the early events of osteoarthritis and might take a part in the repair of cartilage matrix.
TGF-beta-induced G2/M delay in proliferating rabbit articular chondrocytes is associated with an enhancement of replication rate and a cAMP decrease: possible involvement of pertussis toxin-sensitive pathway.
Vivien D, Galéra P, Lebrun E, Daireaux M, Loyau G, Pujol JP
J Cell Physiol 0021-9541
PMID : 1346400
KEYWORDS : Adenylate Cyclase Toxin|Animals|Cartilage, Articular|cytology|Cell Cycle|drug effects|Cholera Toxin|pharmacology|Cyclic AMP|metabolism|DNA Replication|drug effects|Flow Cytometry|In Vitro Techniques|Nuclear Proteins|metabolism|Pertussis Toxin|Proliferating Cell Nuclear Antigen|Rabbits|Transforming Growth Factor beta|pharmacology|Virulence Factors, Bordetella|pharmacology
Show abstract [+]
This study was undertaken to gain more insight into the mechanism whereby TGF-beta influences the cell cycle progression of cultured rabbit articular chondrocytes. Using proliferating chondrocytes in fetal calf serum-containing medium, we have previously shown that TGF-beta induced a recruitment of cells at the end of the S phase (G2/M) observed 24 h after addition. The delayed cells may then be released, producing a proliferative effect at 48 h, provided a substantial amount of FCS (10%) is present in the medium. Otherwise, in low level of serum (2% FCS, for example), only inhibition of cell proliferation is observed. In chondrocytes synchronized in S phase by a thymidine block, we investigated here the time-course incorporation of [3H]-thymidine into DNA, the cell cycle traverse by flow cytofluorometric study of DNA content, the expression of PCNA (Proliferating Cell Nuclear Antigen), and cAMP levels. The data demonstrate that TGF-beta provoked a decrease of cAMP content (0.5-1 h) followed by an enhancement of the DNA synthesis rate (4 h) which was detectable through cytofluorometric analysis and [3H]-thymidine labeling and correlated with the PCNA expression. In contrast, addition of cAMP analogues to the cultures resulted in an inhibition of replication rate. We also showed that pertussis toxin produced a decrease of the DNA synthesis rate, in a transient manner and only in the presence of TGF-beta. All these results suggest that TGF-beta may accelerate the replication process of cyclized chondrocytes, making then accumulate at the G2/M boundary, via a mechanism that could involve the adenylate cyclase activity and a Gi-protein. The factor might be responsible for producing a pool of cells having already replicated their DNA and therefore capable of re-entering the cell cycle without delay. This cell population could serve as a tissue reserve able to induce a mitosis wave when necessary--for example, in the repair of tissue damage.
1991
Differential response of cultured rabbit articular chondrocytes (RAC) to transforming growth factor beta (TGF-beta)-evidence for a role of serum factors.
Vivien D, Galera P, Loyau G, Pujol JP
Eur J Cell Biol 0171-9335
PMID : 1879436
KEYWORDS : Animals|Blood|Cartilage, Articular|cytology|Cell Cycle|drug effects|Cell Division|drug effects|Cells, Cultured|Culture Media|DNA|biosynthesis|Epidermal Growth Factor|pharmacology|Kinetics|Platelet-Derived Growth Factor|pharmacology|Rabbits|Transforming Growth Factor beta|pharmacology
Show abstract [+]
We show that addition of TGF-beta (0.01-10 ng/ml) to proliferating rabbit articular chondrocytes in presence of low level of fetal calf serum (FCS, 2%) results in a sustained decrease of cell number and DNA synthesis up to 72 h. In contrast, incubation with high serum concentration (10% FCS) induces a transient increase of cell number after 48 h without elevation of DNA synthesis. Moreover, when the factor is added in 10% FCS-containing medium, a differential effect is observed at 48 h (either increase or decrease of cell number) depending on the serum level (2 or 10%) present between 24 and 48 h. Recruitment of cells in late S-phase occurred under TGF-beta-treatment in both 2 and 10% FCS. These arrested cells may then be released by further exposure to 10% FCS-containing medium. The data show that factor(s) from the serum modulate(s) the action of TGF-beta on chondrocyte proliferation. Addition of epidermal growth factor (EGF) to the cultures in presence of 2% FCS mimicks the effects observed with 10% serum, suggesting that the serum component(s) involved in the mechanism could be of EGF type.
1990
Differential effects of transforming growth factor-beta and epidermal growth factor on the cell cycle of cultured rabbit articular chondrocytes.
Vivien D, Galéra P, Lebrun E, Loyau G, Pujol JP
J Cell Physiol 0021-9541
PMID : 2358472
KEYWORDS : Animals|Cartilage, Articular|cytology|Cell Cycle|drug effects|Cell Division|drug effects|Cells, Cultured|DNA|biosynthesis|Epidermal Growth Factor|pharmacology|Plateletpheresis|Rabbits|Transforming Growth Factors|pharmacology
Show abstract [+]
We examined the effect of transforming growth factor (TGF-beta) on the proliferative rate and cell cycle of cultured rabbit articular chondrocytes using cell counting, cytofluorometry, and [3H]-thymidine incorporation. In the presence of 2% or 10% FCS (fetal calf serum), TGF-beta at 0.01, 0.1, 1, and 10 ng/ml had an inhibitory effect on cell proliferation after 24 h exposure with a dose dependence only for 2% FCS. Flow cytometric analysis of cell DNA content at that time showed that a high proportion of cells were arrested in late S-phase (SQ or G2Q) in either 2% or 10% FCS-containing medium. In both cases, a disappearance of the cell blockage occurred between 24 and 48 h after TGF-beta addition. However, whereas a stimulation of cell proliferation rate was observed at that time in cultures containing 10% FCS, a dose-dependence inhibition of cell growth was detected, in contrast, for 2% FCS-treated cells. Presence of TGF-beta during the last 24 h was not necessary to release the arrested cells. Furthermore, platelet-poor plasma at 10% produced the same effects as FCS, suggesting that platelet-derived factors, such as platelet-derived growth factor (PDGF), could not be responsible for the release of blocked cells in this case. We compared the effect of TGF-beta to that of epidermal growth factor (EGF), used at an optimal concentration (10 ng/ml). In both slowly growing (2% FCS) and proliferating chondrocytes (10% FCS), EGF caused a significant increase of cell proliferation as early as 24 h. No arrest in late S-phase but an augmentation of the percentage of cells in S- and G2M-phases were observed. When combined, TGF-beta and EGF did not induce synergistic effect on the chondrocyte proliferation, as estimated by cell counting. [3H]-thymidine labeling showed that the factors induced identical maxima of incorporation but the peak occurred earlier for TGF-beta than for EGF (approximately 6 h versus 12 h, respectively). Although both factors induce similar cell-number increases at 48 h in 10% FCS-containing medium, these proliferative effects were due to different actions on the cell cycle. The present study indicates that TGF-beta induces first a recruitment of chondrocytes in noncycling SQ- or G2Q-blocked cells. The, the release of these cells may produce either apparent stimulation of cell proliferation if sufficient levels of an unknown serum factor are present (10% FCS) or an inhibition of growth rate when only reduced amounts of this factor are available (2% FCS).(ABSTRACT TRUNCATED AT 400 WORDS)
