Cerebral ischemia induces the selective synthesis of stress proteins, including the 72,000 heat-shock protein (hspt2). We have demonstrated that focal induction of hsp72 in the cerebral cortex is associated with a profound increase in the tolerance of neurons to a subsequent episode of ischemia. The objective of the present proposal is to identify the mechanisms that contribute to this neuroprotection. Our central hypothesis is that hspt2 is'a major factor in ischemic tolerance. In addition, we hypothesize that induction of neurotrophic factors may also contribute importantly to the neuroprotection. These hypotheses will be tested using the strategy of focal preconditioning of the cerebral cortex followed by transient forebrain ischemia in the rat. The cortex will be preconditioned with brief (20 min) occlusion of the distal middle cerebral artery or with KCl- stimulated spreading depression (SD). SD induces brain-derived neurotrophic factor (BDNF), but not hspt2. To detect alterations in ischemic tolerance, the forebrain is rendered ischemic for 10 min-, and neuronal injury in the preconditioned cortex is compared with that in the contralateral cortex. To investigate the mechanism of neuroprotection, the effect of preconditioning on the decline of ATE during forebrain ischemia will be determined. In. addition, we will determine whether preconditioning alters the expression of hspt2 -A or recovery of protein synthesis following forebrain ischemia. Finally, we will determine whether antisense oligodeoxynucleotides can specifically block expression of hsp72 and whether viral vectors carrying the hsp72 gene can be --used to focally overexpress hsp72.
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