GLUCOCORTICOIDS AND ISCHEMIC CELL DEATH

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Transient forebrain ischemia occurs whenever blood flow to the brain stops for a period of time and then is restarted. In patients, transient forebrain ischemia occurs with cardiac arrest, drowning, or anesthetic accidents followed by successful resuscitation. Transient forebrain ischemia is associated with delayed and selective neuronal death in the CA/1 region of the hippocampus. While other brain regions may also show evidence of damage, the CA/1 regions seems particularly susceptible to transient ischemia. We have studied the regulation of CA/1 pyramidal cell death by glucocorticoids. We found that adrenalectomy even as late as 24 hours after a brief episode of ischemia results in significant protection of CA/1 neurons. Our preliminary data suggests that there is a post- ischemic surge in glucocorticoids which substantially contributes to the amount of CA/1 pyramidal cell death. The objectives of this proposal are the logical progression of these preliminary experiments. We will test the hypothesis that glucocorticoids affect the rate of CA/1 death rather than the absolute amount of damage by carefully examining the time course of CA/1 damage after various interventions which will either increase or decrease circulating glucocorticoid levels. We will then test the hypothesis that the glucocorticoid effects are independent of changes in brain temperature. Finally we will examine the hypothesis that ischemic cell death represents a form of programmed cell death. We will look for DNA fragmentation in the CA/1 pyramidal layer and examine the time course of glucocorticoid receptor translocation after transient ischemia. We will study the effect of protein synthesis inhibition on CA/1 damage. In these experiments, we will pay special attention to the timing of fragmentation, receptor translocation and the effects of protein synthesis inhibition. We will determine the effect of changes in brain temperature and plasma glucocorticoids on this timing. These experiments will extend our observations on the role of glucocorticoids in ischemic cell damage and should provide useful insights into the molecular basis of ischemic cell death. Ischemic cell death in CA/1 appears to be an important consequence of cardiac arrest in humans and may prove a useful model for studying the penumbra around focal cerebral infarction. Thus the experiments proposed here should provide a rationale for pharmacological interventions that might be used in combination with other agents to prevent brain damage in patient with cardiac arrest and stroke.