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

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 (␤1-24 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 shamoperated 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 cytochromeIndeed PREG was found in the brain, at concentrations about 1 order of magnitude larger than those of DHEA, as might be expected from a precursor-to-product relationship (5). The concentrations of PREG and of its sulfate ester PREGS were of the same order of magnitude, and about 10-fold larger than in plasma. They were found at least in part independent of the activity of steroidogenic glands.Solid evidence has been accrued for the biosynthesis of PREG in the nervous system (reviewed in ref. 6). Incubation of primary cultures of rat forebrain glial cells with a precursor to cholesterol led to the formation of cholesterol, PREG, progesterone, and 20␣-dihydro-PREG, and incubation of rat oligodendrocyte mitochondria with cholesterol yielded pregnenolone (7,8). There is only one cholesterol side-chain cleavage enzyme, named cytochrome P450 scc , with strong structural similarity between rodent, bovine, and human species. The presence of immunoreactive P450 scc protein in the rat and human brain has been established in the white matter and in primary cultures of the newborn rat forebrain glial cells (9).However, the abundance of P450 scc mRNA is exceedingly low and could be demonstrated only by reverse transcription-PCR (RT-PCR) (10-12).Major efforts were devoted to the elucidation of DHEA biosynthesis in the brain (13). However, incubations of [ 3 H]PREG (and sulfated or acetyl ester derivative...

Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7α‐hydroxylase and 17‐ketosteroid reductase activity in the human brain

“…In the rodent brain, the formation of DHEA metabolites with reduced pyridine nucleotides as coenzymes is primarily catalysed via 7a-hydroxylase and 17b-HSD activity (Baulieu and Robel 1996). The present study is the first to demonstrate and characterize the in vitro metabolism of DHEA via 7a-hydroxylase and 17b-HSD activity in the human CNS.…”

“…Humans show considerably higher plasma and brain tissue DHEA levels than rodents (de Peretti and Forest 1976;Fehér et al 1977;Cutler et al 1978;Corpechot et al 1981;Lanthier and Patwardhan 1986) and the compound is known to accumulate within the brain (Baulieu and Robel 1996). Given this and assuming a catabolic function of brain tissue DHEA 7a-hydroxylase, one should expect a higher 7a-hydroxylase activity in human brain tissue than in rodent brain tissue.…”

“…obesity, chronic fatigue syndrome, AIDS and Alzheimer's disease is a topic of ongoing scientific discussion (Baulieu 1996;Khorram 1996;Watson et al 1996;Hinson and Raven 1999;Williams 2000). Both compounds were reported to accumulate in the brain and are important factors for vitality, development and functions of the CNS (Majewska 1995;Baulieu and Robel 1996;Compagnone and Mellon 1998;Herbert 1998;Garcia-Estrada et al 1999;Li et al 2001). They were found to be subject to a series of enzymemediated conversions within the rodent CNS (Baulieu and Robel 1996).…”

“…Both compounds were reported to accumulate in the brain and are important factors for vitality, development and functions of the CNS (Majewska 1995;Baulieu and Robel 1996;Compagnone and Mellon 1998;Herbert 1998;Garcia-Estrada et al 1999;Li et al 2001). They were found to be subject to a series of enzymemediated conversions within the rodent CNS (Baulieu and Robel 1996).…”

“…With reduced pyridine nucleotides as coenzymes, DHEA is known to be primarily metabolized via 7a-hydroxylase (EC 1.14.13) and 17b-hydroxysteroid dehydrogenase (17b-HSD; EC 1.1.1.62) activity within the rodent brain (Baulieu and Robel 1996). Both reactions require reduced pyridine nucleotides as coenzymes and lead to the formation of androst-5-ene-3b,7a-diol-17-one (7a-hydroxy-DHEA) and androst-5-ene-3b,17b-diol (D5-androstenediol), respectively.…”