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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...

Previous work from our laboratory has shown prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion in mice by 17beta-estradiol, progesterone, and raloxifene. Dehydroepiandrosterone (DHEA), a neurosteroid, was shown to have neuroprotective activities in various paradigms of neuronal death but its effect in vivo in mice on MPTP toxicity has not been reported. We investigated the effects of 17beta-estradiol (2 microg/day) and DHEA (3 mg/day) for 5 days before and after an acute treatment of four MPTP (10 mg/kg) injections in male C57Bl/6 mice. Striatal DA concentrations and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC. MPTP mice that received 17beta-estradiol or DHEA had striatal DA, DOPAC, and HVA concentrations comparable to intact animals and higher than striatal DA, DOPAC, and HVA levels in saline-MPTP-treated mice. MPTP treatment led to an increase of striatal DA turnover (assessed with the HVA/DA ratio); DHEA and 17beta-estradiol prevented this increase. 17beta-Estradiol did not affect striatal DA and metabolites concentrations in intact mice in this paradigm. Furthermore, in the substantia nigra DHEA and 17beta-estradiol prevented the MPTP-induced dopamine transporter and tyrosine hydroxylase mRNA decreases measured by in situ hybridization. Therefore, DHEA such as 17beta-estradiol is active in preventing the catecholamine-depleting effect of MPTP and our results suggest that this involves neuroprotection of DA neurons.

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