?s abstract): The overall objective of this proposal is to test the hypothesis that free radicals generated during cerebral ischemia and reperfusion play a significant role in brain injury by either attacking tissue or by affecting gene expression of inflammatory mediators, including the cytokines and proteases. Although a significant amount evidence exists to implicate involvement of free radicals in the pathophysiology of cerebral ischernic damage, the detailed mechanism of the oxidative injury cascade is still poorly understood. The investigators will first test a hypothesis that cerebral ischermia and reperfusion significantly enhance the generation of free radicals in the region of ischemia, by quantitatively measuring the time course of concentration changes of nitric oxide, superoxide, and peroxynitrite in the middle cerebral artery occlusion (MCAo) rat model during the pre-ischemic, post-ischemic, and post-reperfusion periods, using the non-invasive in vivo electron paramagnetic resonance (EPR) techniques. Secondly, they will test a hypothesis that regions of early ischemic damage that can be detected with diffusion and perfusion MRI correspond to the regions of increased free radical and protease production, by carrying out diffusion and perfusion MRI monitoring of brain tissue at various time points following an MCAo and comparing the results with those from an EPR and histological study. Thirdly, they will test a hypothesis that free-radical production alters the induction and activation of matrix metalloproteinases (MAPS) by their effects on the nuclear transcription factors following MCAo, by measuring the time course of the formation of cytokines and MAPS that are affected by NF-KB following MCAo. Lastly, they will test a hypothesis that pharmacological interventions aimed at decreasing the generation of specific free radicals will result in decreased formation of MAPS, leading to decreased cerebral damage, by examining the effects of agents that interfere selectively with free radical and MMP productions on neuronal death, blood brain barrier damage and infarct volume in the core and penumbra. Successful accomplishment of the proposed aims will provide fundamental mechanistic information regarding the free radical-mediated tissue injury, and will elucidate important molecular targets for possible intervention. These studies will both reveal and test potential novel pharmacological intervention strategies for reducing the brain injury following cerebral ischemia.
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