Stereospecific prevention by 17 beta-estradiol of MPTP-induced dopamine depletion in mice

Neuroprotective activity of estrogens is reported in Alzheimer disease and recently has also been suggested for Parkinson disease, a disease affecting more men than women. To characterize this estrogenic activity, we studied the effects of 17 beta- and 17 alpha-estradiol treatment (1 mu g twice dail y 5 days before, during the day of four MPTP (15 mg/kg) injections, and for the following 5 days) on dopamine striatal toxicity induced by the neuroto xin MPTP in retired breeder male C57BL/6 mice. Striatal dopamine concentrat ions and its metabolites dihydroxyphenylacetic acid and homovanillic acid m easured by HPLC in MPTP mice that received 17 beta-estradiol were comparabl e to control animals, whereas MPTP mice treated with saline or 17 alpha-est radiol showed important decreases of dopamine and its metabolites. Striatal serotonin and its metabolite 5-hydroxyindoleacetic acid concentrations rem ained unchanged after MPTP and treatments with steroids. Striatal [H-3]GBR 12935 binding autoradiography to the dopamine transporter was as extensivel y decreased and correlated with dopamine depletion in MPTP mice, whereas th is transporter mRNA decrease in the substantia nigra pars compacta was less pronounced. Treatment with steroids did not significantly change [H-3]GBR 12935 binding, whereas dopamine transporter mRNA levels were not significan tly different from controls. Under the present paradigm in retired breeder male mice, our results show dopaminergic and stereospecificity of estradiol to augment dopamine levels in MPTP-lesioned mice without protecting agains t the extensive loss of dopamine terminals and moderate cell body loss. (C) 2000 Wiley-Liss, Inc.