Estrogen attenuates the MPTP-induced loss of dopamine neurons from the mouse SNc despite a lack of estrogen receptors (ERalpha and ERbeta).

Estrogen attenuates the loss of dopamine from striatum and dopamine neurons from the substantia nigra (SNc) in animal models of Parkinson's disease. Interestingly, estrogen receptors (ERalpha and ERbeta) are thought to be sparse or absent in mouse striatum and SNc. Since ERalpha is markedly induced in rodent cortex after ischemic injury, the present studies evaluated changes in ERs after acute treatment with the dopamine neurotoxin MPTP. Mice were injected daily with estradiol, injected with MPTP on day 6, and brains collected on day 9 or 13. Immunocytochemistry was then used to assess tyrosine hydroxylase (TH) in striatum and investigate the localization of ERalpha and ERbeta in the striatum and SNc. In addition, cryostat sections were hybridized with a riboprobe complementary to ERalpha or ERbeta mRNA. Evaluation of TH immunoreactivity revealed a dense network of fibers in the striatum of vehicle-treated animals, while a near complete loss of terminals was seen after MPTP treatment. When, however, mice were pretreated with estradiol, the MPTP-induced loss of TH was attenuated. Evaluation of ERalpha and ERbeta in the SNc and striatum demonstrated a sparse localization of both ERs in vehicle-treated mice, a pattern that did not change in animals treated with vehicle/MPTP or estradiol/MPTP. These data demonstrate that ERs are sparse in the mouse striatum and SNc and show that this pattern does not change after MPTP intoxication. This observation and the finding that estrogen affords some protection against MPTP suggest that estrogen may act via nuclear receptor independent mechanisms to protect dopamine neurons from toxins such as MPTP.