常压高浓度氧联合乙醇降低脑缺血后氧化应激损伤的神经保护作用及机制

项目名称： 常压高浓度氧联合乙醇降低脑缺血后氧化应激损伤的神经保护作用及机制

项目编号： No.81501141

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 耿晓坤

作者单位： 首都医科大学

项目金额： 21万元

中文摘要： 脑梗死后组织缺血缺氧坏死，导致神经功能障碍。常压高浓度氧（NBO）能快速通过血脑屏障，改善缺血组织含氧量，被认为是极符合逻辑的神经保护策略之一，但临床研究并未证实其疗效，相反可能加重脑损伤。有研究表明NBO能引起过多自由基（ROS）生成，加剧氧化应激。我们研究发现NBO与乙醇联合应用能够抑制这种副作用，但其作用机制并不清楚。线粒体呼吸是细胞内ROS主要来源，细胞色素c氧化酶（CcO）通过电子传递产生的跨膜质子电化学势能差∆Ψm直接调控线粒体ROS生成。基于以往的研究和预实验结果，我们推测：乙醇通过抑制CcO活性，遏制线粒体∆Ψm超极化，阻断了NBO可能加剧氧化应激的作用途径，转入氧化磷酸化途径，增加ATP生成，改善能量代谢，发挥神经保护作用。本课题将从在体动物和细胞水平，运用分子生物学方法，结合神经功能测定，验证该假说，揭示NBO通过与乙醇联合应用，在脑缺血后抑制氧化应激损伤的作用机制。

中文关键词： 缺血性卒中；氧化应激；常压高浓度氧；乙醇；细胞色素c氧化酶

英文摘要： The result of ischemic stroke is deprivation of oxygen and glucose leading to rapid ATP decrease, which, in turn, activates multiple damaging processes. Accordingly, oxygen administration, such as normobaric oxygenation (NBO), has been considered as a potential therapy for stroke. Unfortunately, its clinical application has shown relatively low efficacy with higher mortality. In addition to the short time window and weak therapeutic effect in both transient and permanent focal ischemia, higher oxygen concentrations may increase oxidative stress associated with excessive production of reactive oxygen species (ROS), which is a fundamental mechanism of brain damage in ischemia and reperfusion after stroke. Our recent research has revealed a NBO combined with ethanol induced an additive neuroprotection with reduced ROS production. However the underlying mechanisms remain to be elucidated. Ischemia-activated cytochrome c oxidase (CcO), the proposed rate-limiting enzyme of the electron transport chain, becomes hyperactive, leading to mitochondrial membrane potential (ΔΨm) hyperpolarization, which is known to result in excessive ROS at reperfusion when O2 reaches the ischemic tissue. Oxidative stress resulting from hyperactive CcO ultimately causes cell death. Therefore, in the present study, we hypothesize that ethanol stabilizes dysfunctional metabolic pathways mediated by CcO in ischemia, while NBO may enhance its effects on improving aerobic metabolism, leading to attenuated oxidative injury and ameliorated functional outcome. Because both NBO and ethanol are both easily delivered into ischemic brain through the collateral circulation and easily cross the blood brain barrier (BBB), understanding the neuroprotective potential of combining these two metabolic therapies may lead to development of an effective stroke therapy.

英文关键词： Ischemic stroke;Oxidative stress;Normobaric oxygenation;Ethanol;Cytochrome c oxidase