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.

TitleRaloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice.
Publication TypeJournal Article
Year of Publication2014
AuteursBourque, M, Morissette, M, Di Paolo, T
JournalNeurobiol Aging
Volume35
Issue10
Pagination2347-56
Date Published2014 Oct
ISSN1558-1497
Keywords1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Brain-Derived Neurotrophic Factor, Corpus Striatum, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopaminergic Neurons, Estradiol, Male, Mice, Inbred C57BL, Neuroprotective Agents, Proto-Oncogene Proteins c-akt, Raloxifene Hydrochloride, Receptors, Estrogen, Receptors, G-Protein-Coupled, Signal Transduction
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.

DOI10.1016/j.neurobiolaging.2014.03.017
Alternate JournalNeurobiol. Aging
PubMed ID24726471
Grant List / / Canadian Institutes of Health Research / Canada