[Age related changes in cellular signal transduction of glucocorticoid hormones in rat brain]

Chronic or repeated stress can induce a damage of neurons, especially in hippocampus, by which the degree of damage differs in various species. Sapolski has reported that there is a correlation between hippocampal degeneration, disturbed feedback reaction, and hypersecretion of glucocorticoids. The aim of this study was to investigate if the signal transmission via glucocorticoid receptors (GR) in the brain of male wistar rats of two age groups (5-6 and 17-24 months, respectively) is changed in aging and which cytoplasmic factors/modulators participate in this process. The binding of 3H-dexamethasone to cytosolic GR, the transformation, translocation, and nuclear binding of GR complexes (GRC) were studied before and after physiological stress. The influence of cytoplasmic modulators ASTP1) and HSP 70(1)), isolated from brain cytosol and purified, and of exogenous PK C1) was also tested in parallel incubation systems. Whereas old control animals showed a higher cytosolic concentration of unoccupied GR than young ones, this was significantly reduced only in old stressed rats 60 min after stress compared to old controls. The part of transformed GRC, bound to isolated nuclei, was somewhat lower in old than in young rats before and after stress. The nuclear GRC binding could be slightly elevated by addition of ASTP and HSP 70, resp., at the heat transformation of GRC; however, by simultaneous addition of PK C it was significantly increased in both age groups. The GRC binding also rose significantly in stressed animals compared to controls, after simultaneous addition of PK C to more than double of initial assays in young animals. Purified ASTP, isolated from brain cytosol of young animals, showed a higher 32P-incorporation after phosphorylation in vitro than that from old animals. The reduced phosphorylation of ASTP could be one possible cause of the retarded transformation/translocation and the reduced nuclear binding of GRC together with the restricted expression of HSP 70 and decreased PK C activity in the old rat brain.