Role of estrogen receptors in neuroprotection by estradiol against MPTP toxicity.

Estradiol protects against striatal dopamine terminal loss caused by the neurotoxin MPTP in mice. This effect of estradiol is thought to be mediated by an interaction with estrogen receptors (ER), of which there are two: ERalpha and ERbeta. In the present study, the role of these two ERs in MPTP toxicity and its neuroprotection by estradiol was investigated using ER knock out mice (ERKO). MPTP (7, 9, or 11 mg/kg administered four times at 2h intervals) caused a dose-dependent decrease in striatal dopamine and dopamine metabolite DOPAC concentrations in wild type (WT) mice. The degree of dopamine and DOPAC depletion after MPTP was greater in the ERKOalpha mice than WT mice, whereas the ERKObeta mice exhibited no change in MPTP sensitivity. ERKObeta mice showed a lower DA turnover than WT and ERKOalpha mice. WT, ERKOalpha and ERKObeta mice were also treated for 10 days with exogenous estradiol and on day 5 of treatment were challenged with MPTP (9 mg/kg administered four times at 2h intervals). In the WT mice, estradiol partially prevented the MPTP-induced decrease in striatal dopamine and DOPAC concentrations. However, estradiol treatment was without significant neuroprotective effects in the ERKOalpha and ERKObeta mice. These results show a greater susceptibility to MPTP toxicity of ERKOalpha mice compared to WT and ERKObeta mice and a role for both ER receptors in striatal DA neuroprotection.