PMID- 30552945 OWN - NLM STAT- MEDLINE DCOM- 20190902 LR - 20190902 IS - 1872-7972 (Electronic) IS - 0304-3940 (Linking) VI - 696 DP - 2019 Mar 23 TI - The testosterone metabolite 3alpha-androstanediol inhibits oxidative stress-induced ERK phosphorylation and neurotoxicity in SH-SY5Y cells through an MKP3/DUSP6-dependent mechanism. PG - 60-66 LID - S0304-3940(18)30857-7 [pii] LID - 10.1016/j.neulet.2018.12.012 [doi] AB - Testosterone exerts neuroprotective effects on the brain, but the mechanisms by which these effects are exerted appear to be different in males and females. While in females they involve local conversion to estradiol, in males they may be androgen receptor-dependent, or mediated through metabolism to neurosteroids such as 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), which acts through different mechanisms than testosterone itself. Recently, we demonstrated that 3alpha-diol can protect neurons and neuronal-like cells against oxidative stress-induced neurotoxicity associated with prolonged phosphorylation of the extracellular signal-regulated kinase (ERK). The mechanism(s) responsible for these effects remain unknown. In the present study, we sought to determine whether the ERK-specific phosphatase, mitogen-activated protein kinase phosphatase 3/dual specificity phosphatase 6 (MKP3/DUSP6), is involved in the cytoprotective effects of 3alpha-diol in SH-SY5Y human female neuroblastoma cells. 3alpha-diol inhibited ERK phosphorylation and ameliorated cell death induced by the oxidative stressor hydrogen peroxide (H(2)O(2)). These protective effects were significantly reduced by pre-treatment with the MKP3/DUSP6 inhibitor BCI. In addition, H(2)O(2) decreased expression of MKP3/DUSP6, and this was prevented by co-treatment with 3alpha-diol. These findings suggest that the protective effects of 3alpha-diol are mediated through regulation of ERK phosphorylation in neurotoxic conditions and indicate that these effects may be exerted through modulation of MKP3/DUSP6. Targeting the regulation of MKP3/DUSP6 may be beneficial in reducing toxicity under conditions of oxidative stress. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Mendell, Ari Loren AU - Mendell AL AD - Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G 2W1, Canada. Electronic address: amendell@uoguelph.ca. FAU - MacLusky, Neil James AU - MacLusky NJ AD - Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G 2W1, Canada. Electronic address: nmaclusk@uoguelph.ca. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181212 PL - Ireland TA - Neurosci Lett JT - Neuroscience letters JID - 7600130 RN - 0 (Neurotransmitter Agents) RN - 0 (Receptors, Androgen) RN - 3XMK78S47O (Testosterone) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3.1.3.48 (DUSP6 protein, human) RN - EC 3.1.3.48 (Dual Specificity Phosphatase 6) SB - IM MH - Dual Specificity Phosphatase 6/*metabolism MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Humans MH - Hydrogen Peroxide/metabolism/*pharmacology MH - Neurons/drug effects/metabolism MH - Neurotransmitter Agents/metabolism MH - Oxidative Stress/drug effects MH - Phosphorylation/*drug effects MH - Receptors, Androgen/drug effects/metabolism MH - Testosterone/*metabolism OTO - NOTNLM OT - 3alpha-diol OT - DUSP6 OT - ERK OT - MKP3 OT - Neuroprotection OT - Neurosteroids OT - Neurotoxicity EDAT- 2018/12/16 06:00 MHDA- 2019/09/03 06:00 CRDT- 2018/12/16 06:00 PHST- 2018/09/07 00:00 [received] PHST- 2018/12/04 00:00 [revised] PHST- 2018/12/07 00:00 [accepted] PHST- 2018/12/16 06:00 [pubmed] PHST- 2019/09/03 06:00 [medline] PHST- 2018/12/16 06:00 [entrez] AID - S0304-3940(18)30857-7 [pii] AID - 10.1016/j.neulet.2018.12.012 [doi] PST - ppublish SO - Neurosci Lett. 2019 Mar 23;696:60-66. doi: 10.1016/j.neulet.2018.12.012. Epub 2018 Dec 12.