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

Abstract

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, 4,4Ј,4Љ-(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.Many studies have demonstrated the neuroprotective effects of estradiol in vivo against neurotoxins of the nigrostriatal dopaminergic system (Callier et al., 2000;Dluzen and McDermott, 2000;D'Astous et al., 2004). The molecular mechanisms implicated in the neuroprotection have yet to be described. The aim of the present experiment was to investigate the possible implication of the insulin-like growth factor (IGF-I) signaling pathway in the neuroprotective effects of estradiol because there is a great interdependence between the actions of estradiol, IGF-I, and their respective receptors. Indeed, these molecules interact with one another, via their receptors, and are involved in cross-talking through different signaling pathways (Kahlert et al., 2000). These molecules interact to positively affect neuronal differentiation, neurogenesis, synaptic plasticity, neuroendocrine regulation, and neuroprotection (Cardona-Gomez et al., 2001;Garcia-Segura et al., 2001 ABBREVIATIONS: IGF-I, insulin growth factor I; ER, estrogen receptor; IGF-IR, insulin growth factor receptor; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PPT, 4,4Ј,4...

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

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Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain

“…Several evidences have suggested that the neuroprotective effects of estrogen may be mediated by the activation of phosphatidylinositol-3 kinase (PI3K) signaling pathways and that ERα but not ERβ is involved of this intracellular signaling mechanism (Cardona-Gomez et al 2002a, 2002bMendez et al 2003;D'Astous et al 2006). The odds are that nonnuclear ERα is the isoform responsible of downstream activation of PI3K signaling pathway (Gundlah et al 2000).…”

Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications

“…Along these lines, a number of studies have demonstrated that estrogen is neuroprotective in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal lesions, an animal model of idiopathic PD [130][131][132][133][134][135][136][137][138][139][140]. Estrogen prevented MPTP-induced depletion of striatal dopamine, dopamine transporter binding and expression, decreased the MPTP-induced tyrosine hydroxylase-immunoreactive neuron loss and attenuated the glial activation induced by MPTP [130][131][132][133][134][135][136][137][138][139][140]. The estrogenic steroid principally used in these studies was 17β-estradiol (E2), and its effect on dopamine loss was shown by several studies to be stereospecific, as an isomer with weak estrogenic activity, 17α-estradiol, was ineffective at preventing MPTP-induced dopamine loss [131][132][133].…”