CORTICOSTERONE PROMOTES INCREASED HEME OXYGENASE-2 PROTEIN AND TRANSCRIPT EXPRESSION IN THE NEWBORN RAT-BRAIN

Heme oxygenase-2 (HO-2) is the predominant heme oxygenase isozyme in n eurons in the brain, the enzyme cleaves the heme molecule at the alpha -meso carbon bridge to form CO, Fe and biliverdin. Recently, in the pr omotor region of the HO-2 gene a consensus sequence of the glucocortic oid response element (GRE) has been identified. Presently, we have inv estigated the potential relevance of the GRE to the expression of the isozyme, at the transcript and protein levels, in the 14 day old rat b rain, by examining the effect of postparturition corticosterone treatm ent (4 days, starting 24-36 h after birth) on the developmental patter n of HO-2 expression. Northern blot analysis showed that HO-2 transcri pts (similar to 1.3 and similar to 1.9 kb) in brain increase with age. In many brain nuclei, HO-2 protein, as visualized by immunohistochemi stry, was detected at low levels in neurons in the 14 day old rat brai n. Postparturition exposure to corticosterone resulted in a marked enh ancement of HO-2 immunoreactivity in several neuronal populations, inc luding, among others, the cerebellum, the hippocampal formation, and t he oculomotor and red nuclei. The response to elevated levels of corti costerone was particularly striking in the Purkinje neurons of the cer ebellum and the CA3 region of the hippocampus. This was linked to an i ncrease in gene transcription, as indicated by in situ hybridization a nalysis, which revealed an increase in the signal for HO-2 transcripts in these regions. Elevated levels of heme oxygenase activity and HO-2 protein were consistent with an increase in catalytically active prot ein expression. These data point to the intimate involvement of the ad renal steroids in developmentally-linked HO-2 expression in the neuron s involved in motor function and cognition, and hence, identify a pote ntially important aspect of the adrenal steroids' effect on brain grow th and differentiation.