白藜芦醇抑制星型胶质细胞NADPH oxidase-sPLA2途径对脑缺血再灌注损伤的保护作用及机制

流行病学发现红葡萄酒降低心脑血管疾病发病率与白藜芦醇有关。我们前期研究发现白藜芦醇保护脑缺血再灌注诱导的迟发性神经元死亡及伴随的星型及小胶质细胞增生。还发现NADPH氧化酶和分泌型磷脂酶A2（sPLA2）大量存在于脑缺血半暗带增生的星型胶质细胞，此两种酶的抑制剂保护了缺血再灌注脑损伤。新近体外研究显示：白藜芦醇通过NADPH 氧化酶途径抑制了细胞因子诱导的星型胶质细胞sPLA2 mRNA和蛋白的表达。故本课题提出以下假设：NADPH 氧化酶衍生的ROS促进脑缺血半暗带星型胶质细胞活化及sPLA2表达，白藜芦醇通过抑制星型胶质细胞NADPH oxidase-ROS-sPLA2途径保护缺血再灌注脑损伤。本项目利用局灶脑缺血再灌注模型、星型胶质细胞培养结合氧糖剥夺/复氧损伤模型。通过药理干预，从体内和体外两个层面阐明白藜芦醇脑保护作用的新靶点、新机制。为白藜芦醇防治缺血性脑血管病提供理论依据。

Epidemiologic studies have indicated that moderate consumption of red wine is associated with low incidence of cardiovascular and cerebrovascular diseases, and at least a portion of the effect is ralated to resveratrol, a polyphenolic compounds in red wine. Our previous study has demonstrated that administration of resveratrol significantly decreased cerebral ischemia/reperfuion (I/R) induced-delayed neuronal death (DND) and glial cell activation by its anti-oxidant and anti-inflammatory properties. Recent studies demonstrated that activation of NADPH oxidase (producing superoxide) and induction of sPLA2-IIA (an inflammatory enzyme) play an important role in oxidative and inflammatory responses in neurodegenerative diseases including stroke. Our study showed induction of sPLA2-IIA in reactive astrocytes in the ischemic penumbral area after focal cerebral ischemia. Apocynin and PX-18, inhibitors for NADPH oxidase and sPLA2-IIA, were shown to offer protection against I/R-induced DND. Since resveratrol inhibited cytokines-induced astrocytic NADPH oxidase activation and sPLA2-IIA expression, we hypothesize that NADPH oxidase-derived ROS could promote the activation of sPLA2-IIA expression in reactive astrocytes in cerebral ischemic penumbra, and resveratrol might protect again I/R-induced brain injury by inhibiting astrocytic NADPH oxidase-ROS-sPLA2-IIA pathway. This project will utilize focal cerebral I/R animal model as well as primary cultured astrocyte under oxygen/glucose deprivation/reoxygenation (OGD/R) model to explore the neuroprotective mechanism of resveratrol. The results will provide theoretical basis for neuroprotective effect of resveratrol against ischemic stroke and as an effective therapeutical strategy for the treatment of stroke patients.