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

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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.