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Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL, and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada (M.D., M.M., T.D.P.); and Instituto Cajal, Consejo Superior de Investigaciones Cientificas, Madrid, Spain (P.M., L.M.G.-S.)
The present experiments sought to determine the implication of estrogen receptors (ER
and ER
) 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 17-estradiol, an estrogen receptor (ER) agonist, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol (PPT), or an estrogen receptor (ER) agonist, 5-androsten-3, 17-diol (
5-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; 17-estradiol and PPT but not 5-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 17-estradiol and tended to increase with PPT but not with 5-diol treatments in MPTP mice. Glycogen synthase kinase 3 (GSK3) phosphorylation (at serine 9) was greatly reduced in MPTP mice; this was completely prevented by PPT, whereas 17-estradiol and 5-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, 17-estradiol and PPT increased phosphorylation of striatal Akt and GSK3, whereas the other markers measured remained unchanged. 5-Diol increased GSK3 phosphorylation less than the PPT treatment. These results suggest that a pretreatment with estradiol promoted dopamine neuron survival by activating ER and increasing Akt and GSK3 phosphorylation.
Received for publication September 4, 2005.
Accepted for publication January 24, 2006.
Address correspondence to: Dr. Thérèse Di Paolo, Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL, 2705 Laurier Boulevard, Quebec City, Quebec, Canada G1V 4G2. E-mail: therese.dipaolo{at}crchul.ulaval.ca
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