CORTICOSTERONE HAS A PERMISSIVE EFFECT ON EXPRESSION OF HEME OXYGENASE-1 IN CA1-CA3 NEURONS OF HIPPOCAMPUS IN THERMAL-STRESSED RATS

Activity of the stress protein, heme oxygenase-1 (hsp32; HO-1), produc es carbon monoxide (CO), the potential messenger molecule for excitato ry N-methyl-D-aspartate receptor-mediated events, in the hippocampus. Long-term stress caused by elevated adrenocorticoids induces pathologi cal changes in CA1-CA3 neurons of the hippocampus; the adrenal hormone s also exacerbate damage from stress. In rats chronically treated with corticosterone, we examined expression of HO-1 and its response to th ermal stress in the hippocampus. An unprecedented appearance of scatte red immunoreactive astrocytes marked the molecular layer of the hippoc ampus in corticosterone-treated rats. Steroid treatment showed no disc ernible effect on whole-brain HO-1 mRNA. When these rats were subjecte d to hyperthermia, neurons in the CA1-CA3 area, including pyramidal ce lls, exhibited intense immunoreactivity for the oxygenase and a pronou nced increase (similar to 10-fold) in number. HO-1 is essentially unde tectable in this area when rats are exposed to chronic corticosterone alone or thermal stress by itself, or in control rats. In contrast, si milar analysis of hilar neurons showed no apparent effect on either th e number or relative intensity of HO-1-immunostained cells after treat ment. Corticosterone treatment also intensified the stress response of cerebellum, including Purkinje cells and Bergmann glia in the molecul ar layer. In brain, despite a pronounced reduction in NO synthase acti vity in corticosterone-treated and/or heat-stressed animals, the level of cyclic GMP was not significantly reduced. These observations are c onsistent with the hypothesis that responsiveness to environmental str ess of CA1-CA3 neurons brought about by chronic elevation in circulati ng adrenocorticoids results in an increased excitatory neuronal activi ty and eventual hippocampal degeneration. Moreover, these findings yie ld further support for a role of CO in the production of cyclic GMP in the brain.