A large body of experimental evidence supports a role for oxidative stress as a mediator of nerve cell death in Parkinson's disease. To better understand the cellular insult of oxidative stress on dopaminergic neurons, we studied the cytotoxic effect of the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) metabolite, 1-methyl-4-phenyl pyridium (MPP+), on several parameters of cell distress using neuronal PC12 cells. We also measured the level of protein expression for the dopamine transporter and the estrogen receptors α and β. Since estrogens have been reported to prevent neuronal degeneration caused by increased oxidative burden, we investigated the ability of 17β-estradiol, the stereoisomer 17α-estradiol, and several phytoestrogens to rescue neuronal PC12 cells submitted to MPP+-induced cytotoxicity. Our results consistently show a protective effect of 17α-estradiol, 17β-estradiol and certain phytoestrogens such as quercetin and resveratrol, in neuronal PC12 cells treated with MPP+. In our cellular paradigm, phytoestrogens coumestrol, genistein, and kaempferol did not revert MPP+-induced cellular death. By Western blot, we demonstrated that administration of MPP+ alone decrease dopamine transporter expression, while treatments with MPP+ together with 17α-estradiol, 17β-estradiol, quercetin, or resveratrol could restore dopamine transporter protein expression to control levels. Moreover, the same treatments did not modulate α estrogen receptor or β estrogen receptor expression. By these studies, we aim to provide more evidence for the involvement of phytoestrogens in the process of neuroprotection and to test our hypothesis that some of these compounds may act as neuroprotective molecules and have a lesser hormonal effect than estrogens. © 2002 Wiley-Liss, Inc.