Acute ischemic stroke is a major cause of disability especially among the elderly and is the third leading cause of death. Reactive nitrogen species (NO and ONOO') are being increasingly implicated in the pathophysiology of cerebral ischemia-reperfusion injury. Since inducible nitric oxide synthase (iNOS) is a high output enzyme and it is active for days when induced, we hypothesized that NO produced by iNOS is an important factor in the pathophysiology of cerebral ischemia-reperfusion injury. We have identified a number of compounds (N-acetylcysteine, lovastatin, mevastatin and sodium phenylacetic acid) which will inhibit the induction of iNOS and proinflammatory cytokines in brain cells in culture. The proposed studies will test the therapeutic potential of these drugs against cerebral ischemia-reperfusion injury. The first and second specific aims are designed to investigate whether N-acetylcysteine, alpha-lipoic acid and/or lovastatin will block/down regulated the induction of proinflammatory cytokines and iNOS in brain exposed to ischemia/reperfusion injury. The third specific aims is designed to investigate whether N-acetylcysteine or lipoic acid and/or lovastatin will block/down regulate the induction of delayed cell loss by apoptosis in brain exposed to ischemia/reperfusion injury. From these studies we will seek to answer the following questions: 1) Does treatment with the drugs prevent the neuronal injury given prior to the onset of ischemia? 2) Does treatment with the drugs prevent the neuronal injury by altering the course of the disease when given after the ischemic insult. These are relatively nontoxic compounds and are presently being prescribed for human consumption in other diseases. Therefore, demonstration of beneficial effects of these drugs in an animal model of cerebral ischemia-reperfusion injury will help identify the ideal candidates for subsequent use in clinical trials involving cerebral ischemia and stroke.
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