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ABSTRACT: The reproductive properties of estrogen are well established, but it is now evident that this steroid hormone has substantial modulatory capabilities in nonreproductive systems. For example, estrogen may be neuroprotective as Alzheimer's disease progresses more slowly in women receiving hormone replacement therapy, and Parkinson's disease affects more men than women. Gender affects both the functional and biochemical responses of the nigral-striatal pathway to dopaminergically active compounds. To begin to evaluate the possible neuroprotective effects of estrogen in this pathway, we first determined if gender affected the dopaminergic striatal neurotoxicity induced by two different neurotoxicants, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH). Both agents induced greater neurotoxicity in males than females as evidenced by greater striatal dopamine (DA) depletions. An examination of striatal levels of 1-methyl-4-phenylpyridium ion (MPP+) following MPTP treatment established that the observed gender differences were not due to metabolic/pharmacokinetic variables. The neurotoxicity of MPTP was then examined in ovariectomized (OVX) mice. Estrogen replacement reduced the DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletions as well as the glial fibrillary acidic protein (GFAP) elevation induced by MPTP, which indicates that estrogen has neuroprotective properties in this model of striatal dopaminergic neurotoxicity. Surprisingly, estrogen supplementation did not protect against the neurotoxic effects of MPTP in intact 2-yr-old intact female mice, suggesting that low endogenous levels of estrogen may provide neuroprotection.