Neuroprotection by estrogen against MPP+-induced dopamine neuron death is mediated by ERalpha in primary cultures of mouse mesencephalon.

Estrogen involvement in neuroprotection is now widely accepted, although the specific molecular and cellular mechanisms of estrogen action in neuroprotection remain unclear. This study examines estrogenic effects in a mixed population of cells in attempts to identify the contributing cells that result in estrogen-mediated neuroprotection. Utilizing primary mesencephalic neurons, we found expression of both estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) with a predominance of ERalpha on both dopamine neurons and astrocytes. We also found that 17beta-estradiol protects dopamine neurons from injury induced by the complex I inhibitor, 1-methyl-4-phenyl pyridinium (MPP(+)) in a time- and ER-dependent manner. At least 4 h of estrogen pre-treatment was required to elicit protection, an effect that was blocked by the ER antagonist, ICI 182,780. Moreover, ERalpha mediated the protection afforded by estrogen since only the ERalpha agonist, HPTE, but not the ERbeta agonist, DPN, protected against dopamine cell loss. Since glial cells were shown to express significant levels of ERalpha, we investigated a possible indirect mechanism of estrogen-mediated neuroprotection through glial cell interaction. Removal of glial cells from the cultures by application of the mitotic inhibitor, 5-fluoro-2'-deoxyuridine, significantly reduced the neuroprotective effects of estrogen. These data indicate that neuroprotection provided by estrogen against MPP(+) toxicity is mediated by ERalpha and involves an interplay among at least two cell types.