Neurosteroids: Regional steroidogenesis

Abstract

An enzymatic activity of cytochrome P450 was first identified as a component of adrenal steroidogenesis by Estabrook and his coworkers in 1963. The adrenal glands and gonads synthesize large amounts of steroid hormones and secrete them for systemic circulation. Two decades later, regional steroidogenesis in the brain was well established by Baulieu and his coworkers. Brain-synthesized steroids were termed neurosteroids. Recently, regional steroidogenesis has been reported in various organs, including the heart, lung, pancreas, and intestine. The locally synthesized steroids are present at low levels and may function as paracrine modulators. Neurosteroids exert various important modulatory effects on brain functions and diseases. This chapter presents evidence for the regulation of neurosteroidogenesis and the protective functions of brain-synthesized steroids in the rat hippocampus. (1) Rat hippocampal cultured slices synthesized testosterone and 17β-estradiol as neurosteroids. Retinoic acid stimulated the synthesis of sex steroids via transcriptional activation of cytochromes P450(17α) and P450arom. (2) The housing conditions of immature rats strongly affected the hippocampal steroid synthesis by alteration of mRNA levels for steroidogenic enzymes. (3) De novo synthesized estradiol self-protected rat hippocampal cultured slices from methylmercury toxicity by an estrogen receptor-mediated mechanism. (4) The neuroprotective effect of progesterone against tributyltin in the rat hippocampal slices was not mediated by a progesterone receptor but by allopregnanolone, which was synthesized from progesterone.