Characterisation of antioxidant pathways involving Gpx-1: Implications for neural ischemic reperfusion injury.

中风后的神经损伤可分为两个阶段。第一种发生在缺血损伤后，导致神经细胞活力迅速丧失；第二阶段（通常导致严重的神经功能障碍）发生在再灌注后的数小时内。然而，在缺血再灌注后不久，如果有适当的治疗干预，可以将脑损伤降至最低。然而，我们识别新靶点和制定中风治疗策略的能力依赖于我们对(a)脑缺血后启动的分子过程和(b)再灌注和低灌注后延迟的分子事件并导致广泛的神经元损失的理解。伴随中风的一个主要因素是氧化应激的产生。活性氧（ROS）被认为在缺血后的早期和晚期对神经元细胞损伤和死亡有重要贡献。因此，参与ROS生成的分子途径是开发改进疗法的主要目标。我们已经确定抗氧化酶谷胱甘肽过氧化物酶-1 （Gpx-1）在保护神经元免受缺血性损伤-死亡中起重要作用。更清楚地了解Gpx-1如何在体内提供这种保护，将对改进治疗方案的设计做出重要贡献。在本提案中，我们计划确定Gpx-1在中风体内模型中的作用：(1)在更广泛的意义上证明这种抗氧化酶在神经元存活中的功能重要性；(2)以更具体的方式证明这种酶对两种信号分子PI3K激酶（PI3K）和NFkB（两者都是氧化还原敏感的，在神经元细胞活力中起重要作用）的影响及其与缺血性细胞损伤和死亡的相关性。

Neural damage following stroke can be grouped into two stages. The first occurs immediately following the ischemic insult and results in the rapid loss of neural cell viability; the second stage (which usually results in severe neural dysfunction) occurs over many hours following reperfusion. There is however, a window of opportunity shortly following the ischemia-reperfusion where damage to the brain can be minimized if appropriate therapeutic intervention was available. However, our ability to identify novel targets and devise strategies for the treatment of stroke relies on our understanding of (a) the molecular processes that are initiated following brain ischemia and (b) the delayed molecular events that follow reperfusion and hypoperfusion and result in extensive neuronal loss. A major component that accompanies stroke is the generation of oxidative stress. Reactive oxygen species (ROS) are thought to make a significant contribution to neuronal cell injury and death during both the early and late stages following ischemia. Therefore the molecular pathways that are involved in ROS generation are prime targets for the development of improved therapies. It has already been established by us that the antioxidant enzyme, glutathione peroxidase-1 (Gpx-1) is essential in protecting neurons from ischemic injury-death. A clearer understanding of how Gpx-1 confers this protection in vivo would make an important contribution towards the design of improved treatments. In this proposal, we plan to determine the role of Gpx-1 in an in vivo model of stroke to: (1) demonstrate in a broader sense the functional importance of this antioxidant enzyme in neuronal survival and (2) to demonstrate in a more specific manner, the impact of this enzyme on two signaling molecules, PI3kinase (PI3K) and NFkB (both of which are redox sensitive and play important roles in neuronal cell viability) and their relevance to ischemic cell injury and death.