FREE RADICAL INJURY IN REVERSIBLE BRAIN ISCHEMIA

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Stroke is the most common life-threatening neurologic disease. There are an estimated 2.0 million stroke survivors (American Heart Association, 1986), many requiring costly acute and chronic multidisciplinary care. Despite increasing knowledge of the biochemistry, pathophysiology, and clinical manifestation of cerebral ischemia, we have no effective acute pharmacologic intervention to offer patients. The most typical stroke syndrome is caused by embolic occlusion of the middle cerebral artery. Acute embolic occlusion is commonly followed by resolution of the clot by endogenous fibrinolytic mechanisms, allowing for reperfusion of the ischemic tissue. Paradoxically, reperfusion may incur injury through the proposed production of oxygen free radicals. The role of free radicals in acute ischemic neuronal injury remains elusive, mostly due to the technical difficulty of measuring the various short-lived free radical species in vivo. Additionally, reliable focal ischemic models have been difficult to establish. The aim of this research proposal is to elucidate the role of oxygen free radicals during reversible focal ischemia, by characterizing their temporal and spatial characteristics during and after ischemic conditions and by understanding their relationship to known excitatory amino acids and nitric oxide related mechanisms. Latter years will focus on elucidating specific targets of free radical species including the role of neuronal mitochondria in acute ischemic damage. Specifically these experiments will couple the well established technique, brain tissue microdialysis, to a reliable focal ischemia model in the rat. This experimental design allows for the in situ recovery of stable free radical adducts, and the administration of pharmacological substances. Pilot studies have demonstrated technical feasiblity. A better understanding of the in vivo role of oxygen free radicals in ischemic neuronal death would lead to the development of highly specific exogenous free radical scavengers or the ability to pharmacologically manipulate known modulatory factors. The ultimate result would be reduced stroke mortality, morbidity and fiscal costs.