GLUCOCORTICOIDS REGULATE PROTEIN-SYNTHESIS IN HIPPOCAMPAL SLICES UNDER MILD HEAT-SHOCK CONDITIONS

Glucocorticoid hormones potentiate the toxic effects of neuronal stres sors, Alteration of gene expression by glucocorticoids could contribut e to neuronal susceptibility by downregulating the synthesis of protei ns necessary to adapt to challenge. Using heat shock of hippocampal sl ices as a model for cellular insult, protein synthesis has been examin ed in response to acute glucocorticoid administration to rats. Incubat ion of hippocampal slices at 39 degrees C produces a heat-shock patter n of protein synthesis in that total incorporation of labeled amino ac id is diminished, whereas synthesis of the major heat-shock proteins, HSP90 and HSP70, is increased. Prior administration of corticosterone to rats does not affect subsequent synthesis of HSP90 or HSP70 in slic es. However, at 4 or 24 h following a single corticosterone injection, the synthesis of two acidic proteins is found to be altered:a 25-kDa protein is downregulated in the nuclear and synaptosomal-mitochondrial fraction of the hippocampus, and a 47-kDa protein is downregulated in all three fractions of the hippocampus, cortex, and cerebellum These effects are mimicked by administration of RU-28362, a specific glucoco rticoid (GR or Type II) receptor agonist. Since decreased synthesis of p25 and p47 is the only glucocorticoid-mediated response observed in slices under heat-shock conditions, these proteins may be related to t he adaptation to heat shock.