BRAIN REPERFUSION INJURY--ENERGY STATE & FREE RADICALS

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The long term objectives of this proposal are to: (a) develop a small animal model of global ischemia, and (b) use this model to test current hypotheses concerning reduction of reperfusion brain injury by pharmacologic means. Both objectives are directly related to common and clinically important circumstances of brain ischemia and reperfusion injury; for example, cardiac arrest with hypoxic/ischemic encephalopathy. Specific Aims related to these two objectives (all five years of the award) are: (1) to combine the techniques of microwave enzyme inactivation and nuclear magnetic resonance (NMR) spectroscopy to quantitate changes in high-energy intermediates in short-term cerebral ischemia in gerbils; (2) test the hypothesis that the rate of energy utilization at the onset of ischemia determines subsequent recovery of high-energy metabolism with re- perfusion; (3) relate in vitro metabolic changes to observation of in vitro phosphorous and proton nuclear magnetic resonance spectra in ischemia and re-perfusion; (4) develop methods for assessment of oxygen free radical production and morphologic ischemic cell change and correlate these measures with the energy state of the brain, and (5) assess therapeutic interventions, such as allopurinol, for prevention of re- perfusion injury using the fully developed animal model. The experiments are based on a repeated measures design; the basic statistical method used is analysis of variance for a factorial experiment. A final long term objective is to gain teaching experience in the area of stroke and nuclear magnetic resonance applications in neurology. This will be achieved by teaching graduate level courses in nuclear magnetic resonance and neuroscience, and participating in the clinical teaching activities of the Department of Neurology.