Tamoxifen eliminates estrogen's neuroprotective effect upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system.

The capacity for 17-alpha and 17-Beta estradiol to modulate MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system and potential antagonism of this modulation by the anti-estrogen, tamoxifen, were evaluated. Treatment of retired breeder ovariectomized C57/Bl mice with 17-Beta estradiol diminished the amount of striatal dopamine reduction resulting from MPTP treatment with striatal dopamine concentrations of these 17-Beta estradiol treated mice failing to differ significantly from vehicle treated controls. A combined administration of 17-Beta estradiol with tamoxifen abolished this neuroprotective effect of estrogen as striatal dopamine concentrations of this group were significantly lower than vehicle treated controls. Results to 17-alpha estradiol were less effective since striatal dopamine concentrations of these mice following MPTP treatment were significantly decreased as compared with vehicle controls. In contrast to the nigrostriatal dopaminergic system, no statistically significant effects of these treatments were observed upon olfactory bulb dopamine concentrations. Taken together, these results show that 17-Beta, but not an equivalent concentration of 17-alpha estradiol was effective in decreasing striatal dopamine neurotoxicity to MPTP. This effect of 17-Beta estradiol was abolished by tamoxifen. These data have important implications regarding the mechanisms of estrogen-tamoxifen interactions within the nigrostriatal dopaminergic system as well as for clinical applications of tamoxifen within pre-menopausal women.