The goal of this research program is to further examine the role of nitric oxide (NO) in ischemic brain injury. NO is synthesized by the enzyme NO synthase and is involved in a wide variety of physiological and pathological processes. Studies during the previous funding period have demonstrated that the inducible or """"""""immunologic"""""""" isoform of NO synthase (iNOS) is expressed in the brain of rodents and humans following cerebral ischemia, and that NO produced by iNOS contributes to ischemic brain injury in rodents. Cyclooxygenase-2 (COX-2), a prostaglandin-synthesizing enzyme that is induced during inflammation, is also unregulated following cerebral ischemia, and its reaction products contribute to cerebral ischemic damage. These studies have indicated that iNOS and COX-2 are important pathogenic factors in the late stages of cerebral ischemia. There is evidence that NO can activate COX-2, thereby increasing COX-2 production of toxic prostanoids and reactive oxygen species. It is therefore conceivable that the interaction between NO and COX-2 contributes to the deleterious effects of iNOS-derived NO following cerebral ischemia. In this renewal application, studies are proposed to test the hypothesis that iNOS- derived NO enhances COX-2 catalytic output and that COX-2 reaction products are a critical factor by which iNOS-derived NO mediates ischemic brain injury. The proposed experiments will use molecular and biochemical approaches, as well as methods to assess histological and neurological outcome after cerebral ischemia, to test this hypothesis. Focal cerebral ischemia will be produced by occlusion of the middle cerebral artery in rat and iNOS-deficient mice. These studies will continue to expand our understanding of the role of NO in ischemic brain injury and may provide the rational basis for new therapeutic strategies for human stroke.
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