3 research outputs found

    Stratégies de neuroprotection et de régénération à la suite d'une ischémie cérébrale chez le rat

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    Actuellement, l ischémie cérébrale reste un problème majeur de santé publique puisqu elle représente la troisième cause de mortalité et la première cause de morbidité dans les pays industrialisés. Bien que la thrombolyse soit utilisée, un nombre limité de patients ayant subi une ischémie cérébrale bénéficie de ce traitement en raison de sa courte fenêtre d intervention et du risque hémorragique. Plusieurs traitements neuroprotecteurs se sont montrés efficaces à la suite d une ischémie cérébrale au cours d essais pré-cliniques mais cet effet n a pas été retrouvé au cours d essais cliniques. Les recherches se sont également orientées vers des traitements régénérateurs qui peuvent être administrés tardivement à la suite d une ischémie cérébrale. Mes travaux de thèse ont consisté à évaluer deux stratégies thérapeutiques, une stratégie neuroprotectrice en utilisant un inhibiteur de la c-Jun N-terminal kinase (JNK), le D-JNKi, et une autre régénératrice en combinant à la fois l administration de cellules souches mésenchymateuses et d érythropoïétine, dans un modèle d ischémie cérébrale focale transitoire chez le rat. Ces études avaient pour but d agir à la fois au cours de la phase aiguë de l ischémie cérébrale en limitant ainsi la mort neuronale mais également au cours de la phase tardive en favorisant la réparation du tissu lésé en stimulant notamment la formation de nouveaux neurones dans les régions lésées. Afin d étudier le potentiel bénéfique des différents traitements, nous avons privilégié l évaluation de la récupération fonctionnelle, qui reste le critère le plus important en clinique par comparaison à la taille de lésion.Currently, cerebral ischemia remains a major problem of public health since it represents the third cause of mortality and the first cause of morbidity in the industrialized countries. Although thrombolysis is available, a limited number of patients suffering of cerebral ischemia are treated due to its short therapeutic window and its haemorrhagic risk. Several neuroprotective treatments have been shown efficient following cerebral ischemia in pre-clinical trials but this effect was not retrieved in clinical trials. Researches using regenerative treatments that can be administered later after cerebral ischemia were then conducted. My thesis work consisted in the evaluation of two therapeutic strategies, a neuroprotective strategy using an inhibitor of c-Jun N-terminal kinase (JNK), the D-JNKi and a regenerative strategy combining administration of both mesenchymal stem cells with erythropoietin, in a model of transient focal cerebral ischemia in the rat. The aim of these studies was to act not only during the early phase of cerebral ischemia in reducing neuronal death but also during the later phase in favoring the repair of lesioned tissue by stimulating the formation of new neurons. To study the potential benefit of these different treatments, we have particularly paid attention to the assessment of functional recovery, which is the most important criteria in clinic in comparison to the lesion size.CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

    Genetic Background Influence on Hippocampal Synaptic Plasticity: Frequency-Dependent Variations between an Inbred and an Outbred Mice Strain

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    For almost half a century, acute hippocampal slice preparations have been widely used to investigate anti-amnesic (or promnesic) properties of drug candidates on long-term potentiation (LTP)—a cellular substrate that supports some forms of learning and memory. The large variety of transgenic mice models now available makes the choice of the genetic background when designing experiments crucially important. Furthermore, different behavioral phenotypes were reported between inbred and outbred strains. Notably, some differences in memory performance were emphasized. Despite this, investigations, unfortunately, did not explore electrophysiological properties. In this study, two stimulation paradigms were used to compare LTP in the hippocampal CA1 area of both inbred (C57BL/6) and outbred (NMRI) mice. High-frequency stimulation (HFS) revealed no strain difference, whereas theta-burst stimulation (TBS) resulted in significantly reduced LTP magnitude in NMRI mice. Additionally, we demonstrated that this reduced LTP magnitude (exhibited by NMRI mice) was due to lower responsiveness to theta-frequency during conditioning stimuli. In this paper, we discuss the anatomo-functional correlates that may explain such hippocampal synaptic plasticity divergence, although straightforward evidence is still lacking. Overall, our results support the prime importance of considering the animal model related to the intended electrophysiological experiments and the scientific issues to be addressed

    Combined therapeutic strategy using erythropoietin and mesenchymal stem cells potentiates neurogenesis after transient focal cerebral ischemia in rats.

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    International audienceMany studies showed beneficial effects of either erythropoietin (EPO) or mesenchymal stem cells (MSCs) treatment in cerebral ischemia. In addition to a neuroprotective role, not only EPO but also MSC favors neurogenesis and functional recovery. In an attempt to further improve postischemic tissue repair, we investigated the effect of a systemic administration of MSC, in the presence or not of EPO, on neurogenesis and functional recovery in a transient focal cerebral ischemia model in the adult rat. Twenty-four hours after ischemia, the rats were divided into four groups, namely vehicle, MSC, EPO, and MSC+EPO, and received a single intravenous injection of MSC (2 x 10(6) cells) and/or a repeated intraperitoneal administration of EPO (1,000 UI/kg) for 3 days. The lesion volume, the MSC outcome, neurogenesis, and functional recovery were assessed 51 days after ischemia. The results showed that cellular proliferation and neurogenesis were increased along the lateral ventricle wall in the MSC+EPO group, whereas no significant effect was observed in groups receiving MSC or EPO alone. This effect was accompanied by an improvement of mnesic performances. Mesenchymal stem cells expressing neuronal or glial markers were detected in the ischemic hemisphere. These results suggest that EPO could act in a synergistic way with MSC to potentiate the postischemic neurogenesis
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