Reversible focal cerebral ischemia is an important problem. However the precise mechanisms and their relative importance in accounting for the resulting brain injury are unclear. Considerable recent interest has been devoted to tissue damage due to oxygen-derived free radicals in many organs; however, little data are available for the brain, especially for ischemia. The primary goals of this project are to test the hypothesis that oxygen radicals are generated in brain following focal cerebral ischemia and to determine whether oxygen radical ablation therapy enhances recovery of cerebral function, metabolism and cerebral blood flow. We will utilize the nitroblue tetrazolium technique as an indicator of superoxide anion. (02-) (NMR) spectroscopy to measure steady state and transient changes in cerebral ATP, phosphocreatine, inorganic phosphate, and intracellular pH in the same animal. We will determine the time course of the appearance of (02-) following different duration of cerebral ischemia produced by middle cerebral artery occlusion (MCAO) in cats. The hypothesis that 02- production at reperfusion is increased with ischemic duration, and then decreases as reperfusion proceeds will be tested. We propose to determine the time course and relationship of the rate of return of brain evoked potentials with the rate of return of high energy phosphates and intracellular pH (PHi) following different durations of MCAO. We postulate that the initial rate of recovery of high energy phosphates may be a better indicator of mitochondrial function than simply the eventual return of high energy phosphates to control values, and that this may be a better predictor of recovery of brain electrical function. We will then determine whether free radical scavengers alter the relationship between functional recovery and rate of return of high energy phosphates and PHi in such a way as to be beneficial to the brain. Finally, we will determine whether radical scavengers can be administered at different times following reperfusion and be efficacious, and effect a return towards control of high energy phosphates and pHi. The results of these studies will provide new, important information concerning the potential mechanism of injury with ischemia, and potentially offer ideas for therapeutic interventions.
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