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Identification of molecular targets in the treatment of stroke

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Defense Thèse de privat-docent : Univ. Genève, 2010
Abstract Ischemic stroke is a heterogeneous disorder with a complex pathophysiology. Experimental models of cerebral ischemia may contribute to our understanding of the mechanisms occurring during ischemic brain injury, and therefore be of relevance to detect anti-ischemic molecules against stroke. Although currently thrombolytic agents are the only approved therapy for this disorder, neuroprotection offers a viable strategy to treat acute ischemic stroke patients. The acute neuronal degeneration in the ischemic core upon stroke is followed by a second wave of cell death in the ischemic penumbra and neuroanatomically connected sites. This temporally delayed deleterious event of programmed cell death (also called apoptotic cell death) often exceeds the initial damage of stroke and, thus, contributes to significant losses of neurological functions. Because these events are delayed and potentially reversible, the injured neurons in these regions around the ischemic core zone are salvable and constitute the target of neuroprotective strategies. Therefore, using genetically modified mice, we discuss here novel alternative strategies to abrogate the death cascade in vivo in a model of permanent focal ischemia induced by permanent middle cerebral artery occlusion. Evaluations of these new strategies include two mitochondrial effectors, namely the anti-apoptotic protein Bcl-2, and the uncoupling protein-2 (UCP2), known to attenuate some deleterious effects of ischemia such as oxidative stress and calcium homeostasis alterations. In addition, a nuclear transcription factor, the peroxisome proliferator-activated receptor β(PPARβ), which may regulate the expression of UCP2 and is abundantly expressed in the brain, has recently emerged as a potential tool to limit ischemic injury. Indeed, among the main biologic phenomena thought to be influenced by PPAR activation, cytokine-mediated inflammatory processes and activation of anti-oxidant mechanisms are of key importance for cell damage after acute cerebral ischemia. Finally, it is well described that the so-called "ischemic tolerance" phenomenon could constitute an additional strategy to limit brain damage. Among the potential inducers of ischemic tolerance are the infectious agents. However, results from the literature are conflicting and findings supporting that chronic infection may confer protection against subsequent ischemia warrant further investigations. As chronic murine toxoplasmosis may be of particular interest in the study of infection-related effects on brain ischemia, because of its association with the regulation of the oxidative state as well as activation of pro-inflammatory/anti-inflammatory mechanisms, we have also explored the impact of chronic Toxoplasma gondii infection on brain ischemic injury outcomes. On the basis of these experimental data, the present work supports the idea that exploiting the ability of each of these new molecular strategies to reduce cell death induced by stroke injury might be a valuable perspective in the context of the ongoing efforts to identify therapeutic alternatives for this devastating pathology.
Keywords Permanent cerebral ischemiaMiceCell deathNeuroprotectionOxidative stressInflammation
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DE BILBAO, Fabienne. Identification of molecular targets in the treatment of stroke. Université de Genève. Thèse de privat-docent, 2010. https://archive-ouverte.unige.ch/unige:5340

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Deposited on : 2010-03-04

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