title: Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging.
abstract: The neuroactive steroids dehydroepiandrosterone (DHEA), its sulfate ester DHEAS, and allopregnanolone (Allo) are produced in the adrenals and the brain. Their production rate and levels in serum, brain, and adrenals decrease gradually with advancing age. The decline of their levels was associated with age-related neuronal dysfunction and degeneration, most probably because these steroids protect central nervous system (CNS) neurons against noxious agents. Indeed, DHEA(S) protects rat hippocampal neurons against NMDA-induced excitotoxicity, whereas Allo ameliorates NMDA-induced excitotoxicity in human neurons. These steroids exert also a protective role on the sympathetic nervous system. Indeed, DHEA, DHEAS, and Allo protect chromaffin cells and the sympathoadrenal PC12 cells (an established model for the study of neuronal cell apoptosis and survival) against serum deprivation-induced apoptosis. Their effects are time- and dose-dependent with EC(50) 1.8, 1.1, and 1.5 nM, respectively. The prosurvival effect of DHEA(S) appears to be NMDA-, GABA(A)- sigma1-, or estrogen receptor-independent, and is mediated by G-protein-coupled-specific membrane binding sites. It involves the antiapoptotic Bcl-2 proteins, and the activation of prosurvival transcription factors CREB and NF-kappaB, upstream effectors of the antiapoptotic Bcl-2 protein expression, as well as prosurvival kinase PKCalpha/beta, a posttranslational activator of Bcl-2. Furthermore, they directly stimulate biosynthesis and release of neuroprotective catecholamines, exerting a direct transcriptional effect on tyrosine hydroxylase, and regulating actin depolymerization and submembrane actin filament disassembly, a fast-response cellular system regulating trafficking of catecholamine vesicles. These findings suggest that neurosteroids may act as endogenous neuroprotective factors. The decline of neurosteroid levels during aging may leave the brain unprotected against neurotoxic challenges.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Crete, Heraklion 71110, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Charalampopoulos
authors.forename: Vassiliki-Ismini
authors.initials: VI
authors.lastname: Alexaki
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Minas
authors.forename: Erene
authors.initials: E
authors.lastname: Dermitzaki
authors.forename: Iakovos
authors.initials: I
authors.lastname: Lasaridis
authors.forename: Lina
authors.initials: L
authors.lastname: Vardouli
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Margioris
authors.forename: Elias
authors.initials: E
authors.lastname: Castanas
authors.forename: Achille
authors.initials: A
authors.lastname: Gravanis
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D003687:Dehydroepiandrosterone / Q000276:immunology*; D006801:Humans; D015213:Neuroimmunomodulation / Q000276:immunology; D009474:Neurons / Q000166:cytology / Q000276:immunology*; D011280:Pregnanolone / Q000276:immunology*
chemical_list: D003687:Dehydroepiandrosterone; D011280:Pregnanolone