title: Neuroprotection in Parkinsonian-treated mice via estrogen receptor α activation requires G protein-coupled estrogen receptor 1.
abstract: We have previously shown that estrogen receptors (ER) α activation and G protein-coupled estrogen receptor 1 (GPER1) stimulation reproduce 17β-estradiol protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced toxicity of dopamine neurons in mice. This suggests that both ERα and GPER1 have a major role in mediating protection of dopamine neurons, but also suggests a potential collaboration between these receptors. The present study tested the hypothesis of a potential collaboration between ER α/β and GPER1 in neuroprotection of dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated male mice, using a pharmacologic approach. The ERα/β antagonist, ICI 182,780, blocked the protective effects of 17β-estradiol, but not those of GPER1 agonist G1, on dopamine concentration as well as dopamine transporter and vesicular monoamine transporter 2 specific binding in both the striatum and the substantia nigra. G1 protection was accompanied by an increase in Blc-2 and brain-derived neurotrophic factor (BDNF) levels in the striatum; coadministration of ICI 182,780 blocked the effect of G1 only on BDNF levels. ERα activation by its agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) protected dopamine neurons, an effect associated with activation of striatal Akt signaling and an increase in Bcl-2 and BDNF levels; the GPER1 antagonist G15 inhibited the decrease in glycogen synthase kinase 3β activity and the increase in BDNF induced by PPT. Our results suggest that ERα requires GPER1 in protection of dopamine neurons and modulation of signaling pathways, and that the effect of GPER1 occurs independently of ERα/β, whereas GPER1 require ERα/β to increase BDNF levels.
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Quebec, G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, G1K 7P4, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bourque
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Quebec, G1V 4G2, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Quebec, G1V 4G2, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, G1K 7P4, Canada. Electronic address: therese.dipaolo@crchul.ulaval.ca.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D004967:Estrogens / Q000097:blood / Q000494:pharmacology; D000077267:Fulvestrant; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013256:Steroids / Q000097:blood
chemical_list: D000978:Antiparkinson Agents; D019208:Brain-Derived Neurotrophic Factor; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C532507:GPER1 protein, mouse; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013256:Steroids; D000077267:Fulvestrant; D004958:Estradiol; D004298:Dopamine
keywords: 17β-Estradiol; Akt; Estrogen receptor; GPER1; MPTP; Neuroprotection