Cardiac arrest and stroke are two of the major causes of death and when patients survive it is often with neurological impairment. A massive release of glutamate and aspartate occurs during ischemia, precipitating entry of calcium ions into cells. Resultant effects include a failure of ion pumps, membrane disruption, and the generation, during reperfusion, of toxic oxygen-derived free radicals. The mechanisms underlying ischemia-induced amino acid transmitter release will be studied. Data obtained in this laboratory suggest that this may result from a depolarization-induced reversal of the high affinity, sodium dependent glutamate transporter and not as a calcium-dependent vesicular release. Several experiments are proposed to explore this issue. If glutamate release from ischemic cortical cells is transporter-mediated, it would raise the possibility of using inhibitors of the transporter to control release and injury. Adenine nucleotide loss during ischemia is an important element in the injury process and the rate of recovery of nucleotides during reperfusion is likely to be a significant factor in preventing delayed neuronal death. The loss of adenine nucleotides and their recovery during reperfusion will be measured. Agents which prevent adenosine metabolism will be tested for their """"""""purine sparing and salvage"""""""" potential. A recent dramatic development has been the discovery that cycloheximide, a protein synthesis inhibitor, attenuates damage even when administered 24 hrs postischemia. These studies will be extended to evaluate puromycin, as well as cycloheximide, for cerebroprotective activity using rat and gerbil stroke models. The role of the vasodilator nitric oxide in the regulation of cerebral blood flow and prevention of ischemic injury will be evaluated in rats and gerbils. Studies will be conducted on acetylcholine release from the ischemic cerebral cortex to determine whether or not the pattern parallels that for glutamate and aspartate. The glutamate antagonist atropine, will be tested for cerebroprotective activity. Finally, a study of the susceptibility of female gerbils to cerebral ischemic injury will be compared with that of the males. These experiments will shed further light on the events underlying cerebral ischemic injury and should lead to novel approaches to the prevention and treatment of stroke related damage.
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