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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Corpus Striatum / metabolism
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopaminergic Neurons* / drug effects
  • Estradiol / metabolism
  • Male
  • Mice, Inbred C57BL
  • Neuroprotective Agents / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Raloxifene Hydrochloride / pharmacology*
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled / physiology*
  • Signal Transduction / drug effects*


  • Brain-Derived Neurotrophic Factor
  • Dopamine Plasma Membrane Transport Proteins
  • GPER1 protein, mouse
  • Neuroprotective Agents
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Raloxifene Hydrochloride
  • Estradiol
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Proto-Oncogene Proteins c-akt
  • Dopamine