title: 5α-Androstane-3α,17β-Diol Inhibits Neurotoxicity in SH-SY5Y Human Neuroblastoma Cells and Mouse Primary Cortical Neurons.
abstract: Low free T levels in men are associated with age-related cognitive decline and increased risk for neurotoxicity, resulting in disease. The mechanisms underlying these observations remain poorly defined. Although rapid, androgen receptor-dependent activation of ERK has been postulated as a neurotrophic and neuroprotective mechanism, actions of T metabolites such as 5α-androstane-3α,17β-diol (3α-diol) may also be involved. We investigated the influence of 3α-diol on the induction of ERK phosphorylation in SH-SY5Y human female neuroblastoma cells and primary cortical neurons from male and female mice. In SH-SY5Y cells, ERK phosphorylation was induced by 10 nM DHT, epidermal growth factor, hydrogen peroxide (H2O2), and acetylcholine. The addition of 10 nM 3α-diol, which did not itself activate ERK, significantly inhibited ERK phosphorylation induced by DHT, epidermal growth factor, or H2O2, but not acetylcholine. In both SH-SY5Y cells and primary cortical neurons, prolonged ERK phosphorylation and caspase-3 cleavage resulting from amyloid β-peptide 1-42 (Aβ42) exposure were inhibited by cotreatment with 3α-diol. 3α-diol also reduced the loss in cellular viability induced by Aβ42 or H2O2in SH-SY5Y cells. These data suggest that T-mediated neuroprotection may occur via two distinct but complementary mechanisms: an initial rapid activation of ERK phosphorylation, followed by modulation via 3α-diol of the potentially adverse consequences of prolonged ERK activation.
authors.affiliation: Department of Biomedical Sciences (A.L.M., C.E.C., B.E.K., N.J.M.), Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1.
authors.forename: A L
authors.initials: AL
authors.lastname: Mendell
authors.affiliation: Department of Biomedical Sciences (A.L.M., C.E.C., B.E.K., N.J.M.), Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1.
authors.forename: C E
authors.initials: CE
authors.lastname: Creighton
authors.affiliation: Department of Biomedical Sciences (A.L.M., C.E.C., B.E.K., N.J.M.), Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1.
authors.forename: B E
authors.initials: BE
authors.lastname: Kalisch
authors.affiliation: Department of Biomedical Sciences (A.L.M., C.E.C., B.E.K., N.J.M.), Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: MacLusky
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D015113:Androstane-3,17-diol / Q000494:pharmacology*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D053148:Caspase 3; D000109:Acetylcholine