title: Estrogen receptors and gonadal steroids in vulnerability and protection of dopamine neurons in a mouse model of Parkinson's disease.
abstract: 17β-estradiol is well known to have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We investigated the neuroprotective contribution of estrogen receptors (ERα and ERβ) against MPTP toxicity by examining the membrane dopamine (DA) transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hydroxylase (TH) in ER knock out (ERKO) C57Bl/6 male mice compared to their plasma steroid levels. A dose-response to MPTP comparing wild-type (WT) to ERKO mice was studied. WT mice were also compared to ERKO mice pretreated with 17β-estradiol alone and with MPTP. Specific radioligand binding autoradiography and in situ hybridization for DAT, VMAT2 and TH were assayed in the striatum and the substantia nigra (SN). Intact ERKOβ mice had both striatal transporters levels lower than WT and ERKOα mice. MPTP caused a dose-dependent loss of both striatal transporters that correlated with striatal DA concentrations. Compared to WT and ERKOβ mice, ERKOα mice DAT, VMAT2 and TH were affected at lower MPTP doses. In the striatum and SN, ERKOα mice were more vulnerable and 17β-estradiol protected against MPTP toxicity only in WT mice. ERKOα mice blood plasma had higher levels of testosterone, dihydrotestosterone and 3β-diol compared to the plasma of WT and ERKOβ mice. 17β-estradiol treatment increased estradiol plasma levels in all genotypes. Striatal DA concentrations and SN TH mRNA correlated inversely with plasma testosterone and 3β-diol levels. Hence, in male mice the lack of ERα or ERβ altered their basal plasma steroid levels and both striatal DA transporters as well as their susceptibility to MPTP toxicity.
authors.affiliation: Molecular Endocrinology and Genomic Research Center of CHUQ-CHUL, and Faculty of Pharmacy, Laval University, Quebec City, QC, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Al-Sweidi
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bourque
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000502:physiology*; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D011960:Receptors, Estrogen / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012739:Gonadal Steroid Hormones; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D004958:Estradiol; D004298:Dopamine