Neuroprotective effects of estrogen upon the nigrostriatal dopaminergic system

In this mini-review are first presented data which highlight the capacity and characteristics for estrogen to act as a neuroprotectant of the nigrostriatal dopaminergic system. Estrogen administration significantly attenuates the degree of striatal dopamine depletion to neurotoxins (MPTP, 6-OHDA and methamphetamine) which target the nigrostriatal dopaminergic system. This neuroprotection appears maximal with the 17-beta isomer, but some neuroprotection may also be present with the 17-alpha isomer of estradiol. Treatment with the anti-estrogen, tamoxifen, abolished estrogen's neuroprotective effects upon MPTP or methamphetamine-induced neurotoxicity. Estrogen also preserves striatal dopamine concentrations in gonadectomized male mice treated with MPTP, but neither testosterone nor dihydrotestosterone offer any neuroprotection. A brief review indicating a variety of potential means by which estrogen can function as a neuroprotectant is indicated. Included within this survey are presented estrogen's action as an antioxidant along with its capacity to affect monoamine oxidase, dopamine receptors/release, membrane morphology/fluidity, thermoregulation, blood flow and nitric oxide. This discussion is followed by a more detailed description of estrogen's actions upon the dopamine transporter, which is hypothesized to serve as one of the major mechanism involved with nigrostriatal dopaminergic neuroprotection. Overall, estrogen arrears to inhibit dopamine transporter function by decreasing the affinity of the transporter. Such an effect could prevent neurotoxic agents from entering dopamine nerve terminals, thereby decreasing nigrostriatal neurodegeneration. Finally, some implications regarding this neuroprotectant capacity of estrogen are considered.