Estrogen receptors and gonadal steroids in vulnerability and protection of dopamine neurons in a mouse model of Parkinson’s disease

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-dependant 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.

► Intact ERKOβ mice have striatal DA transporter levels lower than WT and ERKOα.
► ERKOα but not ERKOβ mice have elevated blood plasma androgen concentrations.
► ERKOα mice are more susceptible to MPTP toxicity than WT or ERKOβ mice.
► Neuroprotection against MPTP involves both ERs but ERα activity is dominant.