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Neurobiol Aging. 2014 Oct;35(10):2347-56. doi: 10.1016/j.neurobiolaging.2014.03.017. Epub 2014 Mar 20.

Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice.

Author information

1
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
2
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Quebec, Canada.
3
Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada. Electronic address: therese.dipaolo@crchul.ulaval.ca.

Abstract

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 17β-estradiol. MPTP mice had decreased plasma testosterone, dihydrotestosterone, and 3β-diol levels; this was prevented in raloxifene-treated 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.

KEYWORDS:

Akt; Dopamine; GPER; MPTP; Neuroprotection; Raloxifene; Striatum

[Indexed for MEDLINE]

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