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Neurosteroids as Endogenous Inhibitors of Neuronal Cell Apoptosis in Aging
Author(s) -
CHARALAMPOPOULOS IOANNIS,
ALEXAKI VASSILIKIISMINI,
TSATSANIS CHRISTOS,
MINAS VASSILIS,
DERMITZAKI ERENE,
LASARIDIS IAKOVOS,
VARDOULI LINA,
STOURNARAS CHRISTOS,
MARGIORIS ANDREW N.,
CASTANAS ELIAS,
GRAVANIS ACHILLE
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1366.003
Subject(s) - neuroactive steroid , excitotoxicity , neuroprotection , creb , lactacystin , dehydroepiandrosterone , allopregnanolone , microbiology and biotechnology , chemistry , pregnenolone sulfate , nmda receptor , endocrinology , medicine , biology , receptor , neuroscience , proteasome , transcription factor , gabaa receptor , proteasome inhibitor , biochemistry , androgen , gene , hormone
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‐κB, upstream effectors of the antiapoptotic Bcl‐2 protein expression, as well as prosurvival kinase PKCα/β, 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.