COORDINATE CHANGES IN BRAIN ENERGY METABOLISM AND PROTEIN SYNTHESIS

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Changes in brain energy metabolism and protein synthesis have been studied following transient bilateral ischemia in the gerbil. Project areas include: a) continued characterization of the stress or heat shock response following transient ischemia; b) evaluation of mechanisms responsible for the ischemia-induced depletion of hippocampal dynorphin; and c) mechanisms of overall protein synthesis inhibition and recovery following ischemia. The initial demonstration of increased translation of the major mammalian stress protein, hsp 70, is being extended to the transcriptional level. Preliminary results demonstrate the induction of mRNA's for hsp 70 and ubiquitin, using rat cDNA probes, following hyperthermia in the gerbil, and the effects of ischemia can now be investigated. Immunohistochemical localization of hsp 70 is being pursued with monoclonal antibodies specific for the induced protein. An earlier observation of dynorphin A depletion in gerbil brain following ischemia has been localized exclusively to hippocampus. The time course of changes in peptide levels is consistent with increased activity of the dynorphin-containing dentate granule cells following ischemia. These results extend the concept of hippocampal vulnerability to the neurochemical level, and suggest a role for the intrinsic hippocampal circuitry in proposed excitotoxic mechanisms for loss of hippocampal CA1 neurons following ischemia.