Epidemiological and clinical studies have demonstrated that the prevalence of Parkinson's disease is 1.3 - 3.7 times greater in men than women. In support of this, several studies have also shown that hormone replacement therapy can further reduce the risk of PD in postmenopausal women. Studies in animal models of PD have shown a difference in susceptibility between genders, with males more vulnerable to dopaminergic neurotoxicants. Furthermore, in vivo and in vitro studies have demonstrated that estrogen can reduce the loss of dopamine neurons in several models of PD. In the combined paraquat + maneb (PQ+MB) PD model, where we observe selective loss of SNpc dopamine neurons, female mice are less susceptible to the effects of this combined exposure. Additionally, males pre-treated with estrogenic compounds are protected against the neurotoxic effects of PQ+MB. However, given the side effects of feminizing estrogens, their long-term use in the clinic is problematic. Thus, the development of neuroprotective estrogen analogs that lack the feminizing and hormonal effects of natural estrogen will prove useful in preventing or slowing the degeneration of the nigrostriatal dopaminergic system in PD. This proposal will study several novel non-feminizing analogs of estrogen for their neuroprotective efficacy using the PQ+MB rodent model of PD. Initial studies will screen several novel estrogen analogs in a rat primary mesencephalic culture system and the most potent and efficacious compounds will be further tested in vivo. Additionally, it will be determined whether these compounds can prevent dopamine neuron loss in a progressive dopamine degeneration model.