Recent studies have demonstrated that oxygen radicals such as superoxide, hydroxyl, and nitric oxide, are involved in neuronal cell death following cerebral ischemia and reperfusion. We have demonstrated that cerebral infarction and neurological deficits are significantly ameliorated in transgenic mice overexpressing human CuZn-superoxide dismutase (CuZn-SOD) activity, as compared to their non-transgenic littermates. Other studies have implicated the occurrence of programmed cell death (apoptosis) through internucleosomal DNA fragmentation following cerebral ischemia. Numerous cell culture studies have now suggested that oxidative stress plays a role in programmed cell death, since an overexpressed antioxidant gene such as bcl-2 or a supplement with superoxide dismutase can reduce neuronal cell death through the apoptosis pathway. Our hypothesis is that oxidative stress induced by cerebral ischemia and reperfusion in involved in neuronal cell death through both the necrosis and apoptosis pathways. It is our aim to test our hypothesis using transgenic mice overexpressing human CuZn-SOD (SOD-1) and knockout mutants that contain no (homozygous) or one-half of (heterozygous) SOD-a activity. Since mitochondria is known to be the site of oxygen radicals production, we also hypothesize that increased oxidative stress to mitochondria by either mitochondrial toxins or by the null mutation of mitochondrial manganese SOD (sod-2) in knockout mutants will increase neuronal susceptibility to necrosis and/or apoptosis following cerebral ischemia and reperfusion. In order to dissect out the role of nitric oxide in ischemic brain injury associated with superoxide radicals, various combinations of SOD-1 transgenic and neuronal NOS knockout mutants will be employed. We believe these are unique and fresh approaches that will provide insights into the oxidative mechanisms of the pathogenesis of necrosis and apoptosis following cerebral ischemia and reperfusion.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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