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 5β-androstane-3β,17α-diol (3β-diol) may also be involved. We investigated the influence of 3β-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 3β-diol, which did not itself activate ERK, significantly inhibited ERK phosphorylation induced by DHT, epidermal growth factor, orH2O2, but not acetylcholine. In both SH-SY5Y cells and primary cortical neurons, prolonged ERK phosphorylation and caspase-3 cleavage resulting from amyloid α-peptide 1-42 (Aα42) exposure were inhibited by cotreatment with 3β-diol. 3β-diol also reduced the loss in cellular viability induced by Aα42 or H2O2 in 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 3β-diol of the potentially adverse consequences of prolonged ERK activation.