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

17 beta-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 (ER alpha and ER beta) 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 17 beta-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 ERKO beta mice had both striatal transporters levels lower than WT and ERKO alpha mice. MPTP caused a dose-dependant loss of both striatal transporters that correlated with striatal DA concentrations. Compared to WT and ERKO beta mice, ERKO alpha mice DAT, VMAT2 and TH were affected at lower MPTP doses. In the striatum and SN, ERKO alpha mice were more vulnerable and 17 beta-estradiol protected against MPTP toxicity only in WT mice. ERKO alpha mice blood plasma had higher levels of testosterone, dihydrotestosterone and 3 beta-diol compared to the plasma of WT and ERKO beta mice. 17 beta-estradiol treatment increased estradiol plasma levels in all genotypes. Striatal DA concentrations and SN TH mRNA correlated inversely with plasma testosterone and 3 beta-diol levels. Hence, in male mice the lack of ER alpha or ER beta altered their basal plasma steroid levels and both striatal DA transporters as well as their susceptibility to MPTP toxicity. (C) 2011 Elsevier Ltd. All rights reserved.