Journal
NEUROBIOLOGY OF AGING
Volume 35, Issue 10, Pages 2347-2356Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.03.017
Keywords
Raloxifene; GPER; MPTP; Neuroprotection; Akt; Dopamine; Striatum
Categories
Funding
- Canadian Institutes of Health Research (CIHR)
- Fonds de la Recherche en Sante du Quebec (FRSQ)
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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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