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Molecular Pharmacology

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Research ArticleArticle

Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice

Myreille D'Astous, Pablo Mendez, Marc Morissette, Luis Miguel Garcia-Segura and Thérèse Di Paolo
Molecular Pharmacology April 2006, 69 (4) 1492-1498; DOI: https://doi.org/10.1124/mol.105.018671
Myreille D'Astous
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Pablo Mendez
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Marc Morissette
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Luis Miguel Garcia-Segura
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Thérèse Di Paolo
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Abstract

The present experiments sought to determine the implication of estrogen receptors (ERα and ERβ) 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 17β-estradiol, an estrogen receptor α (ERα) agonist, 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol (PPT), or an estrogen receptor β (ERβ) agonist, 5-androsten-3β, 17β-diol (Δ5-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; 17β-estradiol and PPT but not Δ5-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 17β-estradiol and tended to increase with PPT but not with Δ5-diol treatments in MPTP mice. Glycogen synthase kinase 3β (GSK3β) phosphorylation (at serine 9) was greatly reduced in MPTP mice; this was completely prevented by PPT, whereas 17β-estradiol and Δ5-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, 17β-estradiol and PPT increased phosphorylation of striatal Akt and GSK3β, whereas the other markers measured remained unchanged. Δ5-Diol increased GSK3β phosphorylation less than the PPT treatment. These results suggest that a pretreatment with estradiol promoted dopamine neuron survival by activating ERα and increasing Akt and GSK3β phosphorylation.

  • Received September 4, 2005.
  • Accepted January 24, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (4)
Molecular Pharmacology
Vol. 69, Issue 4
1 Apr 2006
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Research ArticleArticle

Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice

Myreille D'Astous, Pablo Mendez, Marc Morissette, Luis Miguel Garcia-Segura and Thérèse Di Paolo
Molecular Pharmacology April 1, 2006, 69 (4) 1492-1498; DOI: https://doi.org/10.1124/mol.105.018671

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Research ArticleArticle

Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice

Myreille D'Astous, Pablo Mendez, Marc Morissette, Luis Miguel Garcia-Segura and Thérèse Di Paolo
Molecular Pharmacology April 1, 2006, 69 (4) 1492-1498; DOI: https://doi.org/10.1124/mol.105.018671
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