Neurosurgical procedures requiring general anesthesia put patients at risk of sustaining hypoxic-brain damage. Anesthetic agents that protect against hypoxia can prevent such damage. This project proposes to test a number of anesthetics for their ability to protect against oxygen deprivation. We have developed a system that uses the in vitro hippocampal slice to study hypoxic damage in brain tissue. The hippocampus is ideally suited for hypoxic studies since it contains neurons that are extremely sensitive to hypoxia. This in vitro system can accurately quantify electrophysiological damage allowing small differences in the protective efficacy of various agents to be ascertained. Additionally we can measure biochemical parameters from the same cell groups that have been studied electrophysiologically allowing correlation between the protective efficacy of an agent and the biochemical alterations that it produces. Accordingly this system is ideal for studying the cellular physiology of hypoxic damage and the mechanisms of protection against such damage. We will measure the percent recovery of evoked population spike, ATP, PCr, Ca influx, Ca efflux, intracellular Na and intracellular K levels with different neuroanesthetics. These values will be measured separately for the CA1 pyramidal and dentate granule cell layers. In addition to the obvious benefit of finding which currently available anesthetics protect best, a clarification of the mechanisms of hypoxic damage will enable a more rational search for new 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 the cellular mechanisms by which anesthetics protect against anoxic damage.
