Neurosteroid 7-hydroxylation products in the brain.

The neurosteroids pregnenolone (PREG) and dehydroepiandrosterone (DHEA) are precursors for both oxidized and hydroxylated metabolites in the brain. Thus, brain production of 7-hydroxylated derivatives is second to that in the liver, and P4507B1-containing hippocampus is the major site for 7 alpha-hydroxylation. Other P450s and/or oxido-reductive mechanisms may be responsible for 7 beta-hydroxylation. In addition to regulating neurosteroid brain levels, when produced, the 7-hydroxylated derivatives of PREG and DHEA were investigated for antiglucocorticoid-mediated neuroprotective potencies, and both 7 alpha- and 7 beta-hydroxy-DHEA were efficient in preventing the nuclear uptake of [3H]dexamethasone-activated glucocorticoid receptor in brain cells. Activation of 7 alpha-hydroxylation by increased close contacts of astrocytes and after glucocorticoid treatment suggested that the regulated production of 7 alpha-hydroxysteroids was a key event for the neuroprotection conferred by neurosteroids.