The present experiments sought to determine the implication of estrogen receptors (ERalpha and ERbeta) and their interaction with insulin-like growth factor receptor (IGF-IR) signaling pathways in neuroprotection by estradiol against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. C57BL/6 male mice were pretreated for 5 days with 17beta-estradiol, an estrogen receptor alpha (ERalpha) agonist, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol (PPT), or an estrogen receptor beta (ERbeta) agonist, 5-androsten-3beta, 17beta-diol (Delta5-diol). On day 5, mice received MPTP (9 mg/kg) or saline injections, and estrogenic treatments were continued for 5 more days. MPTP decreased striatal dopamine, measured by high-performance liquid chromatography, to 59% of control values; 17beta-estradiol and PPT but not Delta5-diol protected against this depletion. MPTP increased IGF-IR measured by Western blot, which was prevented by PPT. The phosphorylation of protein kinase B (Akt) (at serine 473), an essential mediator of IGF-I neuroprotective actions, increased after 17beta-estradiol and tended to increase with PPT but not with Delta5-diol treatments in MPTP mice. Glycogen synthase kinase 3beta (GSK3beta) phosphorylation (at serine 9) was greatly reduced in MPTP mice; this was completely prevented by PPT, whereas 17beta-estradiol and Delta5-diol treatments were less effective. The ratio between the levels of striatal Bcl-2 and BAD proteins, two apoptotic regulators, decreased after MPTP treatment. This effect was effectively prevented only in the animals treated with PPT. In nonlesioned mice, 17beta-estradiol and PPT increased phosphorylation of striatal Akt and GSK3beta, whereas the other markers measured remained unchanged. Delta5-Diol increased GSK3beta phosphorylation less than the PPT treatment. These results suggest that a pretreatment with estradiol promoted dopamine neuron survival by activating ERalpha and increasing Akt and GSK3beta phosphorylation.