It is well-established that a brief period of global brain ischemia causes delayed cell death in hippocampal CA1 pyramidal neurons days after reperfusion in animals and humans. Although numerous factors have been indicated in this phenomenon, the mechanisms underlying this delayed neuronal cell death are still poorly understood. We have demonstrated that cerebral infarction and neurological deficits are significantly reduced in transgenic mice overexpressing CuZn-superoxide dismutase (Sod1) activity after acute focal stroke, whereas vasogenic edema, infarction and neurological deficits are exacerbated in mutant mice deficient in Sod1 or in mitochondrial manganese SOD (Sod2) activities. But the role of these antioxidant enzymes on the delayed hippocampal neuronal injury after global ischemia is still unknown. Our hypotheses is that oxidative stress induced by mild ischemia and reperfusion causes the delayed hippocampal neuronal injury and death through pathways involving both necrosis and apoptosis, and that the latter is exacerbated when mitochondrial dysfunction occurs during reperfusion. It is our aim to test our hypothesis using transgenic mice overexpressing Sod1 and Sod2 activities and knockout mutant mice that contain no Sod1 -/- (homozygous), half (heterozygous, Sod1 +/-) or Sod2 +/- activities. In order to dissect out the role of neuronal-specific expression of Sod1 in ischemic neuronal protection, we will generate mice that contain only neurons expressing Sod1 activity using neuronal- specific enolase (NSE) promoter with Sod1 genomic DNA construct. In order to elucidate the oxidative role of subcellular compartmentation (i.e., cytosolic vs. mitochondria) in necrosis and apoptosis, we will generate mice that contain genotypes with combinations of increased Sod1 expression and Sod2 +/- knockout mutants. We believe these are unique and fresh approaches that will provide insights into the oxidative mechanism in mitochondria that underlies apoptosis in delayed hippocampal cell death after global cerebral ischemia and reperfusion.
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