Ischemic Preconditioning: mechanisms of neuroprotection

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

DESCRIPTION (provided by applicant): Recent evidence in heart and brain suggest that mild ischemic episodes may limit the damage from subsequent ischemic insults. This program of research is directed toward understanding the mechanisms of such ischemic preconditioning (IPC). In this application, we provide recent data in brain which shows that IPC is mediated by two triggering pathways that intersect at one selective protein kinase C isoform: PKC epsilon. One of these pathways occurs via activation of NMDA receptors. The second path is mediated by the adenosine A1 receptor. The GOAL of proposed research is to increase understanding of the mechanism of IPC by defining the putative role of PKC epsilon in the protection afforded by IPC. Specific aims include: 1) To determine whether preconditioning can be derived during inhibition of one of the two pathways (i.e., NMDA or adenosine) where activation of the other pathway is overstimulated to a threshold above that necessary to trigger preconditioning-induced tolerance. 2) To define the locus of the ePKC translocation in the CA1 region of the hippocampus after IPC. 3) To define the intracellular locus of the ePKC translocation in the CA1 sub-region of the hippocampus after IPC. 4) To define the ePKC effect on synaptic physiology after IPC. The most direct and significant application of understanding the mechanisms of IPC, is that it may provide pharmacological access to this protective state, especially during cardiopulmonary bypass surgery, cardiac transplantation and other types of brain surgeries, where necessary periods of ischemia are provoked in healthy tissue in order to repair other CNS anomalies.