Dehydroepiandrosterone, as endogenous inhibitor of neuronal cell apoptosis: Potential therapeutic implications in neurodegenerative diseases

Abstract

Dehydroepiandrosterone (DHEA) is synthesized in the adrenals and the brain. Additionally, DHEA is produced at high concentrations in the human embryo enhancing neuronal development. Its production rate and levels in serum, brain and adrenals decrease gradually with advancing age. This decline was associated to age-related neuronal dysfunction and degeneration, suggesting a neuroprotective effect of endogenous DHEA against noxious agents. This hypothesis is substantiated by experimental findings showing that DHEA protect neural crest derived cells against serum deprivation-induced apoptosis with EC50 1.8 nM. This potent antiapoptotic effect of DHEA is mediated by G-protein coupled specific membrane binding sites, the subsequent activation of prosurvival kinases Src and PKC and transcription factors CREB and NF-κB, upstream effectors of the antiapoptotic Bcl-2 proteins. These findings suggest that DHEA may act as an endogenous neuroprotective factor, during development and in adulthood. The decline of DHEA levels during ageing may leave the brain unprotected against neurotoxic challenges. The DHEA specific membrane binding sites conferring neuroprotection offer a new target for developing synthetic DHEA analogs with antiapoptotic and neuroprotective properties, deprived of endocrine toxicity. © 2008 Springer Netherlands.