Neuroprotection in Parkinsonian-treated mice via estrogen receptor α activation requires G protein-coupled estrogen receptor 1. (August 2015)

• Record Type: Journal Article
• Authors: Bourque, Mélanie; Morissette, Marc; Di Paolo, Thérèse
• Is Part Of: Neuropharmacology. Volume 95(2015)
• Page Start: 343
• Page End: 352
• Publication Date: 2015-08
• Subjects: 17β-Estradiol -- Estrogen receptor -- GPER1 -- MPTP -- Neuroprotection -- Akt; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2015.04.006
• Languages: English
• ISSNs: 0028-3908

Abstract

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-[1 H ]-pyrazole-1, 3, 5-triyl) tris phenol (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. Highlights: ERα and GPER1 agonists are as potent as 17β-estradiol to protect dopamine neurons. ERα requires GPER1 to induce neuroprotective effects in MPTP-treated mice. Neuroprotection mediated by GPER1 occurs independently of ERα/β. Inhibition of GPER1 blocks the decrease in GSK3β activity induced by ERα activation. The increase in BDNF levels by ERα stimulation is lost when GPER1 is antagonized.