Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids

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Abstract
The observation was made that dehydroepiandrosterone (DHEA), as the unconjugated steroid, and its sulfate ester (DHEAS) are present in the brain of adult male rats (1). This finding was unforeseen because the rodent steroidogenic glands, including the adrenals, do not secrete significant amounts of DHEA (2). It led to the discovery of a steroid biosynthetic machinery in the nervous system, in charge of producing neurosteroids. This term, neurosteroids, was proposed in 1981 (3). It applies to the steroids, the accumulation of which occurs in the nervous system independently, at least in part, of supply by the steroidogenic endocrine glands and which can be synthesized de novo in the nervous system from sterol precursors. The steroid precursors along their biosynthetic pathways can be formed in situ and assayed. This definition applies to DHEA. To demonstrate that brain DHEA is independent of peripheral steroidogenic glands, endocrine manipulations were conducted in rats. Injections for 3 days of long-acting preparations of corticotropin (β1–24 ACTH), to stimulate adrenal steroidogenesis, or of dexamethasone to inhibit endogenous ACTH secretion, were not accompanied by clear-cut changes of brain DHEAS (1). Brain DHEAS was unchanged 1 day after castration, whereas testosterone completely disappeared from the brain. No obvious difference was observed when castrated adrenalectomized males were compared 15 days after operation with sham-operated controls (1, 4). It thus was logical to assume that DHEA synthesis evolves in two steps from cholesterol, as described for steroidogenic glands, principally catalyzed by two different cytochrome P450 enzymes: cholesterol Pregnenolone (PREG) DHEA (Fig. 1). Brain DHEA(S) metabolism. The biosynthesis of PREG and DHEA might proceed from cholesterol either through the classical pathway involving successively cytochromes P450scc and P450c17, or by an alternative pathway involving the intermediacy of sterol and/or steroid hydroperoxides. DHEA is reversibly converted to DHEAS and …