Mitotic and neurogenic effects of dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex

Abstract

Dehydroepiandrosterone (DHEA) is a neurosteroid with potential effects on neurogenesis and neuronal survival in humans. However, most studies on DHEA have been performed in rodents, and there is little direct evidence for biological effects on the human nervous system. Furthermore, the mechanism of its action is unknown. Here, we show that DHEA significantly increased the growth rates of human neural stem cells derived from the fetal cortex and grown with both epidermal growth factor (EGF) and leukemia inhibitory factor (LIF). However, it had no effect on cultures grown in either factor alone, suggesting a specific action on the EGF͞LIF-responsive cell. Precursors of DHEA such as pregnenolone or six of its major metabolites, had no significant effect on proliferation rates. DHEA did not alter the small number (<3%) of newly formed neuroblasts or the large number (>95%) of nestin-positive precursors. However, the number of glial fibrillary acidic protein-positive cells, its mRNA, and protein were significantly increased by DHEA. We found both N-methyl-D-aspartate and sigma 1 antagonists, but not GABA antagonists, could completely eliminate the effects of DHEA on stem cell proliferation. Finally we asked whether the EGF͞LIF͞DHEA-responsive stem cells had an increased potential for neurogenesis and found a 29% increase in neuronal production when compared to cultures grown in EGF͞LIF alone. Together these data suggest that DHEA is involved in the maintenance and division of human neural stem cells. Given the wide availability of this neurosteroid, this finding has important implications for future use.

Linking nutrition to genomics

“…The role of DHEA in human aging has been a matter of long debate (Allolio and Arlt, 2002). DHEA levels peak in the 20 s and drop dramatically afterward, and recently DHEA has been reported to be involved in neuronal survival and maintenance of human neural stem cells (Suzuki et al, 2004). Our gene expression profile of enzymes involved in DHEA metabolism provides a further connection between the starvation response and the anti-aging process.…”

Activities of 3β-HSD and aromatase in slices of developing and adult zebra finch brain

“…It is clear that in both P20 and adult slices, DHEA can be metabolized fully to estrogens and 5α-reduced androgens in this region of the songbird brain. In other vertebrates, DHEA has been shown to influence neurite outgrowth, neuron survival, and adult neurogenesis (Cardounel et al, 1999;Fiore et al, 2004;Karishma and Herbert, 2002;Kimonides et al, 1998;Li et al, 2001;Marx et al, 2000;Suzuki et al, 2004). DHEA has now been detected circulating in the blood of several avian species (Goodson et al, 2005).…”

Neurosteroid regulation of central nervous system development

“…DHEA also promotes neurogenesis and neuronal survival (Karishma and Herbert, 2002;Suzuki et al, 2004). Treatment of rats with DHEA pellets increases neurogenesis in the dentate gyrus.…”