The effects of dehydroepiandrosterone, estradiol and testosterone on 1-methyl-4-phenylpyridium (MPP+)-induced neurotoxicity of the nigrostriatal dopaminergic system were examined in rat. They were subjected to a unilateral intrastriatal infusion of the following treatment conditions: MPP+ alone or co-injection of MPP+ plus each hormone. Four days after injection, concentrations of dopamine and their metabolites were determined from the corpus striatum. To corroborate the neurochemical data an immunohistochemical analysis of tyrosine hydroxylase-immunoreactive fibers and acetylcholinesterase histochemistry in the striatum was performed. Moreover, we performed a dose-response study of the three hormones on the high-affinity dopamine transport system in rat striatal synaptosomes. Rats co-injected within the striatum with MPP+ and either dehydroepiandrosterone or estradiol had significantly greater concentrations of dopamine and less tyrosine hydroxylase-immunoreactive fibers and acetylcholinesterase fiber density loss compared with their respective controls. In addition, 4 days after injection, the brain was fixed and cut into coronal sections, and was immunostained with major histocompatibility complex class II antigens for activated microglia, and glial fibrillary acidic protein for activated astrocytes. Dehydroepiandrosterone also attenuated microglial cell activation. In contrast, testosterone showed reductions in dopamine concentrations similar to those obtained by MPP+. The protective effect of dehydroepiandrosterone against the MPP+ neurotoxic dopaminergic system may be produced by its partial prevention of MPP+ inhibition of NADH oxidase activity, whereas the estradiol may function as a neuroprotectant by reducing the uptake of MPP+ into dopaminergic neurons. Our findings we suggest indicate that dehydroepiandrosterone and estradiol by a non-genomic effect may have an important modulatory action, capable of attenuating degeneration within the striatum, and in this way serve as neuroprotectants of the nigrostriatal dopaminergic system.