Anesthetics and adjuvant drugs must be used for patients undergoing major intracranial operations or requiring cerebral resuscitation after acute brain damage. Anesthetic agents that protect neuronal tissue can minimize damage sustained in these situations. This project proposes to test a number of anesthetics for their ability to protect against oxygen deprivation and investigate the mechanism of anoxic neuronal damage and pharmacologic protection. We have developed a system that uses the in vitro hippocampal slice to study anoxic damage in brain tissue. The hippocampus is ideally suited for anoxic studies since it contains neurons that are extremely sensitive to anoxia. This system can accurately and differentially quantify electrophysiological damage of two hippocampal cell types (CA 1 pyramidal and dentate granule cells), allowing small differences in the protective efficacy of various agents to be ascertained. Additionally, biochemical parameters can be measured from regions containing the cell types studied electrophysiologically, allowing a precise correlation between the protective efficacy of an agent and the biochemical alterations that it produces. Accordingly this system is ideal for studying the cellular mechanisms of anesthetic protection against anoxic damage and offers certain advantages over in vivo studies. The recovery of postsynaptic electrophysiological activity will be measured in the presence of various anesthetics and will be correlated with ATP levels, Ca influx, intracellular Na, K and Ca levels, and free radical formation. Cellular electrophysiological parameters will be examined by recording intracellularly from CA 1 pyramidal cells. By studying the spontaneous neuronal activity in the presence of different drugs and by quantitatively applying neurotransmitter we will try to explain why certain anesthetics provide superior protection against anoxic brain damage. Slices will be subjected to either high glutamate or increased free radical levels to determine if anesthetics interfere with damage due to these insults which have been theorized as being responsible for anoxic and ischemic damage. In addition to the obvious benefit of finding which currently available anesthetics protect best, a clarification of the mechanisms of anoxic damage will enable a more rational search for new drugs or combinations of drugs that will protect even better. Our long term goals are to 1) establish a standardized test for an in vitro assessment of brain protection, 2) discover the relative efficacy of neuroanesthetics for protection against anoxic damage and 3) discover and test the cellular mechanisms by which anesthetics protect against anoxic damage.