Dehydroepiandrosterone: A potential signalling molecule for neocortical organization during development

Abstract

Dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEAS) are the most abundant steroids produced by the human adrenal, but no receptors have been identified for these steroids, and no function for them has been established, other than as precursors for sex steroid synthesis. DHEA and DHEAS are found in brains from many species, and we have shown that enzymes crucial for their synthesis, especially P450c17 (17␣-hydroxylase͞c17,20 lyase), are expressed in a developmentally regulated, region-specific fashion in the developing rodent brain. One region of embryonic expression of P450c17, the neocortical subplate, has been postulated to play a role in guiding cortical projections to their appropriate targets. We therefore determined if products of P450c17 activity, DHEA and DHEAS, regulated the motility and͞or growth of neocortical neurons. In primary cultures of mouse embryonic neocortical neurons, DHEA increased the length of neurites containing the axonal marker Tau-1, and the incidence of varicosities and basket-like process formations in a dose-dependent fashion. These effects could be seen at concentrations normally found in the brain. By contrast, DHEAS had no effect on Tau-1 axonal neurites but increased the length of neurites containing the dendritic marker microtubule-associated protein-2. DHEA rapidly increased free intracellular calcium via activation of Nmethyl-D-aspartate (NMDA) receptors. These studies provide evidence of mechanisms by which DHEA and DHEAS exert biological actions, show that they have specific functions other than as sex steroid precursors, mediate their effects via nonclassic steroid hormone receptors, and suggest that their developmentally regulated synthesis in vivo may play crucial and different roles in organizing the neocortex.Neurosteroids including pregnenolone, allopregnanolone, dehydroepiandrosterone (DHEA), and their sulfated and lipoidal fatty acid ester derivatives are synthesized in the nervous system from cholesterol (1, 2). The same steroidogenic enzymes are found in the nervous system and in the classical steroidogenic tissues (3-9) although their extremely low level of expression in the brain and peripheral nervous system delayed their identification. DHEA and its sulfated derivative (DHEAS) and lipoidal fatty acid ester derivatives are abundant (10 Ϫ8 to 10 Ϫ7 M) in rodent, rabbit, monkey, dog, and human brains (10-14) but expression of P450c17, the sole enzyme having the 17␣ hydroxylase and c17,20 lyase activities needed for DHEA synthesis (15-17) only recently was identified in the fetal but not adult rodent brain (7). Some neurosteroids, such as allopregnanolone and pregnenolone, act through ␥-aminobutyric acid (GABA) A (18-20) receptors while the neurosteroid pregnenolone sulfate may act through NMDA receptors (21, 22) rather than through classical nuclear steroid hormone receptors. Using these neurotransmitter receptors, allopregnanolone elicits anxiolytic, anticonvulsant activity (23, 24). Pregnenolone sulfate, DHEA and DHEAS enhance memory in mi...

Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

“…5-Adiol (Kuiper et al, 1997) and 7-keto-DHEA and a 16-keto-derivative of 5-Adiol (Chang et al (1999) activate the mammalian ER. DHEA, pregnenolone and 7-hydroxy-pregnenolone are neurosteroids (Akawa et al, 1992, Compagnone andMellon, 1998;Baulieu and Robel, 1998). See Lathe (2002) for a more complete discussion of ancestral steroids.…”

“…Mammalian neurosteroids include pregnenolone, DHEA and their analogs (Corpechot et al, 1981;Akawa et al, 1992, Compagnone andMellon, 1998;Baulieu and Robel, 1998;Lathe, 2002). Importantly, Compagnone and Mellon (1998) found that DHEA and its sulfate are important in the development of the rat brain.…”

“…Importantly, Compagnone and Mellon (1998) found that DHEA and its sulfate are important in the development of the rat brain. Our model suggests that modern neurosteroids were ligands for the ancestral ER and PR.…”

“…Moreover, understanding the early events in the evolution of steroidogenic enzymes may shed light on adrenarche (Arlt et al 2002;Rainey et al, 2002) and the actions of neurosteroids (Baulieu and Robel, 1998;Compagnone and Mellon, 1998) in humans.…”

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

“…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).…”