期刊
NEUROBIOLOGY OF AGING
卷 35, 期 10, 页码 2347-2356出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.03.017
关键词
Raloxifene; GPER; MPTP; Neuroprotection; Akt; Dopamine; Striatum
资金
- Canadian Institutes of Health Research (CIHR)
- Fonds de la Recherche en Sante du Quebec (FRSQ)
Raloxifene, used in the clinic, is reported to protect brain dopaminergic neurons in mice. Raloxifene was shown to mediate an effect through the G protein-coupled estrogen receptor 1 (GPER1). We investigated if raloxifene neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice is mediated through GPER1 by using its antagonist G15. Striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid to dopamine ratio as well as dopamine transporter and vesicular monoamine transporter 2 showed that raloxifene neuroprotection of dopaminergic neurons was blocked by G15. Protection by raloxifene was accompanied by activation of striatal Akt signaling (but not ERK1/2 signaling) and increased Bcl-2 and brain-derived neurotrophic factor levels; these effects were abolished by coadministration with G15. The effect of raloxifene was not mediated through increased levels of 17 beta-estradiol. MPTP mice had decreased plasma testosterone, dihydrotestosterone, and 3 beta-diol levels; this was prevented in raloxifeneetreated MPTP mice. Our results suggest that raloxifene acted through GPER1 to mediate Akt activation, increase Bcl-2 and brain-derived neurotrophic factor levels, and protection of dopaminergic neurons and plasma androgens. (C) 2014 Elsevier Inc. All rights reserved.
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