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 neurons in the brain, the enzyme cleaves the heme molecule at the alpha-meso carbon bridge to form CO, Fe and biliverdin. Recently, in the promotor region of the HO-2 gene a consensus sequence of the glucocorticoid response element (GRE) has been identified. Presently, we have investigated the potential relevance of the GRE to the expression of the isozyme, at the transcript and protein levels, in the 14 day old rat brain, by examining the effect of postparturition corticosterone treatment (4 days, starting 24-36 h after birth) on the developmental pattern of HO-2 expression. Northern blot analysis showed that HO-2 transcripts (approximately 1.3 and approximately 1.9 kb) in brain increase with age. In many brain nuclei, HO-2 protein, as visualized by immunohistochemistry, was detected at low levels in neurons in the 14 day old rat brain. Postparturition exposure to corticosterone resulted in a marked enhancement of HO-2 immunoreactivity in several neuronal populations, including, among others, the cerebellum, the hippocampal formation, and the oculomotor and red nuclei. The response to elevated levels of corticosterone was particularly striking in the Purkinje neurons of the cerebellum and the CA3 region of the hippocampus. This was linked to an increase in gene transcription, as indicated by in situ hybridization analysis, 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 protein expression. These data point to the intimate involvement of the adrenal steroids in developmentally-linked HO-2 expression in the neurons involved in motor function and cognition, and hence, identify a potentially important aspect of the adrenal steroids' effect on brain growth and differentiation.