? It is well established that a brief period of global brain ischemia causes delayed cell death in vulnerable hippocampal CA1 pyramidal neurons days after reperfusion in animals and humans. Although numerous factors have been suggested to account for this phenomenon, mechanisms underlying this delayed vulnerability in neuronal death are still poorly understood. We have demonstrated that mitochondria are involved in the early stage of apoptosis by releasing cytochrome c, caspase-9 and second mitochondria-derived activator of caspases after transient global cerebral ischemia. We have also demonstrated that an increase in the cytosolic antioxidant, CuZn-superoxide dismutase (SOD1), in mice and rats significantly ameliorates the molecular and cellular signaling events and the subsequent reduction in delayed hippocampal CA1 neuronal death. We now hypothesize that the level of SOD may serve as a molecular switch to signal the reduction of mitochondrial-dependent cell death and increased survival. However, the mechanisms by which SOD1 influences the cell survival signaling pathways are unknown. It is our goal to test this hypothesis using transgenic (Tg), knockout and double Tg/knockout mice.
Our specific aims are: 1) To elucidate the role of Akt (PKB) as an endogenous neuroprotective signaling pathway after transient global cerebral ischemia; 2) To elucidate the role of oxidative stress and CuZn-superoxide dismutase in survival signaling in hippocampal CA1 neurons after transient global cerebral ischemia; 3) To elucidate the role of mitochondrial oxidative stress in neuroprotective signaling pathways after transient global cerebral ischemia; 4) To elucidate the interplay and compartmentalization of oxidative stress on endogenous neuroprotective signaling in anti-apoptosis in hippocampal CA1 neurons after transient global cerebral ischemia. We believe these are unique and fresh approaches that will provide new insights into the level of antioxidant or oxidative stress as molecular switches for delayed death/survival in hippocampal CA1 neurons after mild global cerebral ischemia. ? ?
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