Study of functional alterations of cerebral endothelial cells in hyperglycemic condition associated to diabetes : protective role of medicinal plant polyphenols ; Étude des altérations fonctionnelles des cellules endothéliales cérébrales en condition hyperglycémique associée au diabète : rôle protecteur des polyphénols de plantes médicinales

In diabetes, hyperglycemia leads to vascular alterations which aggravates cerebrovascular complications such as stroke. In fact, hyperglycemia alters blood-brain barrier integrity that separates the brain and the blood. Cerebral endothelial cells which composed blood-brain barrier are particularly affected by oxidative stress and pro-inflammatory state caused by hyperglycemia. In this context, there is growing interest in the health effects of plant-based polyphenols with antioxidant and anti-inflammatory properties. The objective of the thesis work was to assess the functional alterations of cerebral endothelial cells in hyperglycemic conditions and to determine the protective role of polyphenols extracted from medicinal plants from Réunion. To reach this objective, we have developed a model of murine cerebral endothelial cells exposed to experimental hyperglycemia as well as a model of mice rendered obese and diabetic by a high fat diet and then subjected to a cerebral ischemia-reperfusion by an occlusion of the middle cerebral artery. Polyphenols tested were extracted from four Reunionese medicinal plants traditionally used for anti-diabetic effects. Our results showed that hyperglycemia induced oxidative stress, pro-inflammatory response with monocytic adhesion and deregulation of the production of vasoactive markers in cerebral endothelial cells. In cerebral ischemia, hyperglycemia aggravated the size of the cerebral infarction and the hemorrhagic transformation in obese and diabetic mice. Additionally, hyperglycemia caused redox markers and the blood-brain barrier integrity alteration, and exacerbated neuroinflammation. Several molecular targets have been identified including the antioxidant enzymes Cu / ZnSOD and MnSOD, inflammatory mediators such as IL-6, TNF-a, MCP-1 and E-selectin, vasoactive factors ET-1, eNOS and NO as well as tight junctions ZO-1, ZO-2, claudin-5 and occludin. The role of key signaling pathways contained in NFκB, AMPK, Nrf2 and PPARg has been demonstrated. Importantly, polyphenols ...