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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.)
Received September 4, 2005; accepted January 24, 2006
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Abstract |
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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.
; 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).
Intracellular signaling of IGF-I receptors (IGF-IR) is mediated by the mitogen-activated protein kinase and the phosphatidylinositol-3 kinase (PI3K) pathways (LeRoith et al., 1993; Cardona-Gomez et al., 2002). PI3K promotes the phosphorylation and activation of Akt (also known as protein kinase B), a general mediator of cell survival (Datta et al., 1997). Therefore, activation of IGF-IR leads to the activation of PI3K and Akt. Akt can inhibit apoptosis induced by several stimuli in multiple cell types, acting on various factors influencing cell death, such as members of the Bcl-2 family. Akt regulates Bcl-2 levels (Pugazhenthi et al., 2000) and can phosphorylate and inactivate the proapoptotic protein BAD (Datta et al., 1997). Furthermore, Akt inhibits glycogen synthase kinase 3 (GSK3) activity by increasing its phosphorylation on serines 9 and 21 (Cohen and Frame, 2001). In turn, inhibition of GSK3 is associated with the activation of survival pathways in neurons (Hetman et al., 2000).
The specific estrogen receptor (ER) has been implicated in the activation of the PI3K/Akt pathway (Kahlert et al., 2000; Mendez et al., 2003, 2005). Indeed, only ER interacts with IGF-IR and PI3K in the brain, whereas estrogen receptor (ER) does not participate in such complexes (Mendez et al., 2005). This interaction might represent a way by which estradiol affects IGF-I signaling on the brain. In the present experiments, we sought to determine whether neuroprotection by estradiol against 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP) is mediated by the activation of the PI3K/Akt pathway. Moreover, with specific ER agonists, we determined whether the protective effects of estradiol are dependent on the subtype of the receptor.
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Materials and Methods |
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-estradiol were purchased from Sigma Chemical (St. Louis, MO), 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT) from Tocris (Ellisville, MO), and 5-diol (5-androsten-3,17-diol, also known as 5-androstenediol, androstenediol, or hermaphrodiol) was purchased from Steraloids Inc. (Newport, RI). PPT is a specific ER agonist (Stauffer et al., 2000), whereas 5-diol preferentially binds to and activates ER (Kuiper et al., 1997).
Animals and Treatments. C57BL/6 male mice (10-12 weeks old, 25 ± 2 g) were purchased from Charles River Canada (Montreal, PQ, Canada). Mice were randomly assigned in groups of eight animals. Each group received a 5-day pretreatment of estrogen receptor agonists or vehicle before MPTP injections. The pretreatment consisted of two daily subcutaneous injections (in the dorsal part of the neck) of 17-estradiol, PPT, or 5-diol, whereas control mice received injections of vehicle (0.9% saline with 0.3% gelatin). Concentrations used were 2 µg/day for 17-estradiol and PPT and 3 µg/day for 5-diol as in our previous publication (D'Astous et al., 2004). On day 5, mice received four injections of MPTP (9 mg/kg i.p.) at 2-h intervals, whereas the control group received saline solution. The treatments (estrogenic compounds or vehicle) were continued until day 10, and the next day, the mice were decapitated, and brains were quickly removed and frozen in isopentane (-40°C). In a similar experiment, mice received estrogenic drug treatments for 10 days at the same concentrations as described above, and one group received the vehicle. These groups served as control for the estrogenic treatments and were referred to as intact (nonlesioned) groups because no MPTP lesion was induced in these animals.
The Laval University Animal Care Committee approved all of the animal studies. All efforts were made to minimize animal suffering and to reduce the number of mice used.
Striatal Biogenic Amines Determination. The concentrations of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were measured by high-performance liquid chromatography with electrochemical detection. Supernatants of striatal tissue were directly injected into the chromatograph consisting of a Waters 717 Plus autosampler automatic injector, a Waters 515 pump equipped with a C-18 column (Waters Nova-Pak C18, 3 µm, 3.9 mm x 150 cm; Waters, Milford, MA), a BAS LC-4C electrochemical detector, and a glassy carbon electrode. The mobile phase consisted of 0.025 M citric acid, 1.7 mM 1-heptane-sulfonic acid, and 10% methanol in filtered distilled water delivered at a flow rate of 0.8 ml/min. The final pH of 3.9 was obtained by the addition of NaOH. The electrochemical potential was set at 0.8 V with respect to an Ag/AgCl reference electrode, as described previously (D'Astous et al., 2004).
Western Blot. Striata were dissected and homogenized in lysis buffer (150 mM NaCl, 20 mM Tris-HCl, 10% glycerol, 5 mM EDTA, and 1% Nonidet P-40; Roche, Mannheim, Germany) supplemented with protease and phosphatase inhibitors (50 µg/ml phenylmethyl-sulfonyl fluoride, 10 µg/ml aprotinin, 25 µg/ml leupeptin, and 100 nM orthovanadate; all from Sigma, St. Louis, MO). Homogenates were allowed to solubilize for 30 min on ice and centrifuged at 21,000g for 10 min. Protein content of the supernatant was measured with a modified Bradford assay (Bio-Rad, Munich, Germany).
Proteins were resolved using 10 to 12% SDS-polyacrylamide gel electrophoresis with a Mini-Protean system (Bio-Rad) and electrophoretically transferred to nitrocellulose membranes. The membranes were blocked with 5% nonfat dry milk diluted in 0.05% Tween 20/Tris-buffered saline and incubated overnight with the primary antibodies. The antibodies against IGF-IR (C20; diluted 1:1000), BAD (H168, diluted 1:1000), and Akt (H136, diluted 1:2000) were obtained from Santa Cruz Biotechnologies (Santa Cruz, CA). The monoclonal antibody against Bcl-2 (clone 124, diluted 1:500) was purchased from DAKO A/S (Glostrup, Denmark). Both phospho-specific antibodies against phosphorylated Akt at serine 473 (pSer473Akt, abbreviated as pAkt) and phosphorylated GSK3 at serine 9 (pSer9GSK3, abbreviated as pGSK3) were used at a dilution of 1:1000 and were obtained from Cell Signaling Technology (Beverly, MA). GSK3 monoclonal antibody was from BD PharMingen (San Diego, CA). Finally, III-tubulin antibody was from Promega (Madison, WI). After incubation with the primary antibody, the membranes were washed and incubated with horseradish peroxidase-coupled secondary antibodies (Jackson ImmunoResearch Laboratories Inc., West Grove, PA; diluted 1:10,000). Immunoreactive bands were detected using an enhanced chemiluminescence system (ECL, Amersham Pharmacia Biotech, Little Chalfont, Buckinghamshire, UK). When needed, membranes were stripped using a commercial solution purchased from Chemicon (Temecula, CA). Films were analyzed using the ImageQuant software version 3.22 (computing densitometer model 300A; Molecular Dynamics, Little Chalfont, Buckinghamshire, UK). For Bcl-2, BAD, IGF-IR, GSK3, and Akt, the density of each band was normalized to its respective loading control (-III-tubulin). For pAkt and pGSK3, the total levels of the kinase (Akt or GSK3) were used for normalization. To minimize interassay variations, samples from all animal groups in each experiment were processed in parallel.
Statistical Analysis. Statistical comparisons of data were evaluated using a one-way analysis of variance (ANOVA) using Statview 4.51 for Macintosh (SAS Institute, Cary, NC), followed by a post hoc analysis with the Fisher probability of least significant difference test. Coefficient of correlations and significance of the degree of linear relationship between the variables were determined using a simple regression model using the Statview software. A p value <0.05 was required for the results to be considered statistically significant.
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Results |
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-Estradiol prevented the MPTP-induced dopamine loss. Striatal dopamine concentrations of 5-diol treated MPTP mice were less significantly depleted compared with intact controls than MPTP + vehicle. 5-Diol-treated MPTP mice had significantly lower striatal dopamine and DOPAC concentrations than the MPTP + PPT-treated mice. Striatal concentrations of dopamine, DOPAC, and homovanillic acid of unlesioned mice remained unchanged by the 17-estradiol, PPT, and 5-diol treatments (Table 2).
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Administration of MPTP led to a significant increase in the concentrations of striatal IGF-IR (Fig. 1). Pretreatment with PPT prevented the increase of IGF-IR levels, which were significantly lower than those of MPTP mice. 17-Estradiol and 5-diol-treated MPTP mice had levels that were not different from controls or vehicle-treated MPTP mice. Striatal IGF-IR levels were significantly higher in the MPTP + 5-diol than in the MPTP + PPT group.
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(pGSK3) and at serine residue 473 of Akt (pAkt) were also measured in these groups relative to their unphosphorylated form. Striatal Akt levels remained unchanged after MPTP lesion or estrogenic treatments (Fig. 2). However, in these MPTP mice, pretreatment with 17-estradiol induced a significant increase in pAkt/Akt with regard to control mice. This increase in pAkt/Akt did not reach statistical significance (p = 0.062 versus control) with PPT treatment, whereas 5-diol-treated MPTP mice had lower pAkt/Akt levels than either 17-estradiol- or PPT-treated MPTP mice.
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compared with the control group (Fig. 3). 17-Estradiol and PPT pretreatments prevented this decrease; pGSK3/GSK3 concentrations were significantly higher than the vehicle-treated MPTP group. Moreover, PPT completely spared the decrease of this protein, which was equal to control levels (Fig. 3). 5-Diol- treated MPTP mice had a small increase of pGSK3/GSK3 compared with vehicle-treated MPTP mice, and these levels were lower than estradiol- or PPT-treated MPTP mice.
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-Estradiol- and 5-diol-treated MPTP mice had Bcl-2/BAD ratios that were not different from those of saline- vehicle-treated mice or MPTP mice. 5-Diol-treated MPTP mice had the Bcl-2/BAD ratio lower than the MPTP + PPT- treated mice (Fig. 4).
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-estradiol, PPT, or 5-diol left unchanged the striatal IGF-IR, BAD, or Bcl-2 levels (data not shown). 17-Estradiol and PPT induced an increase in the phosphorylation of Akt and GSK3 (Fig. 5). 5-Diol did not significantly affect the phosphorylated state of Akt (p = 0.126 versus control and p = 0.0558 versus PPT) and increased GSK3 phosphorylation much less than the PPT treatment. There was a tight correlation between the phosphorylation levels of both Akt and GSK3 proteins (r = 0.87), suggesting that there is a functional relationship in response to the estrogenic compounds between these two kinases in mice striatum.
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Discussion |
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). This suggests that atypical mechanisms of action, such as the activation of membrane-associated signaling, are involved in these estrogen receptor-mediated effects. Indeed, high doses of estradiol are necessary to activate the brain PI3K/Akt signaling pathway (Cardona-Gomez et al., 2002), and ER seems to be involved in this effect (Mendez et al., 2003; Cardona-Gomez et al., 2004). Thus, the participation of estrogen receptors in the neuroprotective mechanism may be mediated by the activation of membrane signaling and not by the direct regulation of transcription by binding to estrogen response elements in DNA. The present study investigated whether the PI3K/Akt pathway of signaling is implicated in the neuroprotection after treatment with estrogen agonists. The PI3K/Akt pathway, one of the signaling pathways downstream of IGF-IR, is often linked to cell survival (Datta et al., 1999). Indeed, Akt is a major regulator of cell survival, because it presents regulatory activity on many molecules such as BAD, GSK3 (both known to be proapoptotic factors), and transcription factors such as nuclear factor-
B (Brunet et al., 2001) (Fig. 6).
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The doses and protocol of administration of 17-estradiol and PPT used in this study have been shown previously to prevent MPTP-induced striatal dopamine depletion (D'Astous et al., 2004). Therefore, this is an adequate experimental design to test whether the neuroprotective effect of estradiol and estrogenic ligands is correlated with a modification of the PI3K/Akt signaling pathway. The present study confirms that an ER agonist treatment protects against MPTP-induced striatal dopamine and DOPAC depletion and that this is statistically different from the ER agonist- treated MPTP mice. In addition, 17-estradiol and the ER ligand PPT modulate the expression of IGF-IR. This finding is in agreement with previous studies showing that estradiol and IGF-I coregulate each other and their cognate receptors in the brain (Cardona-Gomez et al., 2001).
Because IGF-IR is coupled to two different signaling pathways leading to cell survival (PI3K/Akt and mitogen-activated protein kinases) (LeRoith et al., 1993; Cardona-Gomez et al., 2002), it is fair to assume that an augmentation in the expression of this receptor contributes positively to cell changes in response to toxic damages. It already has been shown that ER is the only estrogen receptor to coprecipitate with IGF-IR (Kahlert et al., 2000; Mendez et al., 2003). Moreover, neuroprotection by estrogens has been linked to ER activation in different models of toxicity (Dubal et al., 2001; Vegeto et al., 2003; D'Astous et al., 2004). However, in some experimental models, neuroprotection by estradiol is mediated by ER activation (Carswell et al., 2004). ER and ER are detected in the mice striatum (Kuppers and Beyer, 1999) and are shown to remain unchanged after vehicle/MPTP or estradiol/MPTP treatments (Shughrue, 2004). Therefore, although scarce, activation of ER receptor by ER agonists could lead to transcriptional activity and to the regulation of the IGF-IR pathway. Alternatively, other ER-like receptors may convey the ER agonist signal (Hasbi et al., 2005).
Downstream of IGF-IR are the signaling molecules PI3K and Akt, which are both regulated by estrogens (Cardona-Gomez et al., 2002, 2004). It has been demonstrated that estradiol activates Akt in the hippocampus and cortex by increasing its phosphorylation (Cardona-Gomez et al., 2002; Wilson et al., 2002; Znamensky et al., 2003). This could be another way by which estradiol protects cells against damage.
We did not detect significant changes in Akt after treatment with 17-estradiol or ER-selective agonists in control animals or in moderately MPTP lesioned mice, whereas treatment with 17-estradiol or the ER agonist PPT led to important and significant increases in its phosphorylation. Moreover, in intact animals, we showed an increase in Akt phosphorylation after treatment with either 17-estradiol or the ER agonist. In contrast, the ER agonist 5-diol left the phosphorylation of Akt unchanged in both MPTP-lesioned and -unlesioned mice. This could represent a mechanism by which an estrogenic pretreatment leads to a positive modulation of cell survival by the activation of ER. Moreover, this increase in the phosphorylation and activation of prosurvival factors could explain why estradiol pretreatment is necessary to obtain neuroprotection in other neurodegenerative models (Gajjar et al., 2003).
This is the first report linking estradiol striatal dopamine MPTP neuroprotection in mice with IGF-I and Akt signaling pathways. Nevertheless, supporting our findings, Dhandapani et al. (2005) reported recently that transforming growth factor- mediates the neuroprotective effect of estradiol and involves Akt phosphorylation in cultures of primary rat cortical astrocytes. In addition, estrogen was reported to interact with the IGF-I system to protect nigrostriatal dopamine and maintain motor behavior in 6-hydroxydopamine- lesioned rats (Quesada and Micevych, 2004).
GSK3, another molecule studied in the present experiment, may affect neuronal survival by different mechanisms such as the regulation of glucose metabolism (Brunet et al., 2001), phosphorylation of microtubule-associated proteins, or interaction with transcription factors (Cardona-Gomez et al., 2004). GSK3 activity is negatively regulated by the phosphorylation of some of its serines, whereas phosphorylation of tyrosine residues leads to its activation (Cohen and Frame, 2001). Activation of GSK3 results in neuronal apoptosis (Enguita et al., 2005) and is shown to mediate striatal toxin- induced neuronal death (Chen et al., 2004), whereas its inhibition promotes neuronal survival (Cohen and Frame, 2001). Our results indicate that MPTP induces a persistent reduction in the phosphorylation of striatal GSK3 in serines, therefore inducing GSK3 activation. This persistent activation of GSK3 suggests that striatal neuronal death may persist for several days after MPTP treatment. This is in agreement with the persistent expression of striatal inflammatory cytokines in mice several days after the administration of MPTP (Hebert et al., 2003) and with the persistent decrease in the Bcl-2/BAD ratio observed in the present study, an indication of the activation of proapoptotic signaling, because Bcl-2 is an antiapoptotic factor, whereas BAD is proapoptotic (Merry and Korsmeyer, 1997).
17-Estradiol and the ER agonist PPT, and to a lesser extent the ER agonist 5-diol, increase the phosphorylation of GSK3 in serine 9 and, therefore, contribute to its inhibition in the striatum of intact and MPTP-lesioned animals. Because Akt is one of the kinases that inactivates GSK3, the neuroprotective mechanism of 17-estradiol and PPT may involve the ER-mediated activation of Akt and the consecutive inhibition of GSK3 by Akt. Therefore, we propose that inhibition of GSK3 by an ER-mediated mechanism may be involved in the neuroprotective effect of estradiol in this model. Our findings do not exclude that ER may also be involved in neuroprotection. Indeed, the ER agonist 5-diol has a moderate neuroprotective effect. Although 5- diol induced a moderate increase in Akt and GSK3 phosphorylation, ER-mediated neuroprotection may also be exerted through a different mechanism unrelated to the activation of IGF-I signaling.
PPT completely and 17-estradiol or 5-diol partially overcame the decrease in the Bcl-2/BAD ratio induced by MPTP, therefore positively regulating cell survival. An in vitro study demonstrated that PPT and ethyl-3,4-dephostatin (an ER agonist) modulate Bcl-2 levels and promote cell survival in primary hippocampal neurons (Zhao et al., 2004). Bcl-2 expression can be modulated by activation of estrogen-response element and cAMP response element-binding protein (Pugazhenthi et al., 2000), both transcription factors themselves regulated by estrogen in the brain (Abraham et al., 2004). In addition, Akt can induce Bcl-2 transcription (Pugazhenthi et al., 2000). Moreover, Bcl-2 is negatively regulated by BAD.
Many of intracellular molecules measured, such as IGF-IR, BAD, and Bcl-2, were not affected by treatments with estrogen agonists in unlesioned animals. However, important increases in the phosphorylation of both Akt and GSK3 were measured in 17-estradiol- and PPT-treated mice. Moreover, increases in the ratios pAkt/Akt and pGSK3/GSK3 in intact and lesioned animals revealed that changes in these molecules are in favor of cell survival, because both ratios are markers of survival. These changes could indicate which parameters are activated first or are more sensitive to estrogen agonist treatments. We suggest that pretreatment with these molecules contributes to the priming of the survival pathway, both by activating an antiapoptotic molecule, Akt, and by inhibiting a proapoptotic molecule, GSK3. These molecules should therefore be considered as target molecules of 17-estradiol and PPT. Modifications in Akt/GSK3 signaling are reported in individuals with schizophrenia (Emamian et al., 2004). In addition, long-term haloperidol treatment in mice increases phosphorylation of Akt at Ser473 and GSK3 at Ser9 (Emamian et al., 2004), such as reported here with 17-estradiol and PPT. In addition, attenuated 5-hydroxytryptamine-1A receptor signaling involving reduced Akt activity is observed in the occipital cortex of depressed suicide victims (Hsiung et al., 2003). Furthermore, lithium salts used in the treatment of depression in humans are shown to antagonize dopamine-dependent behaviors mediated by an Akt/GSK3 signaling cascade in mice (Beaulieu et al., 2004). Hence, the neuroprotective and neuromodulatory activity of estrogens in animal models and humans may share a common mechanism by affecting Akt/GSK3 signaling.
In conclusion, the present results suggest that the activation of the PI3K/Akt/GSK3 signaling pathway is involved in the neuroprotective effect of estradiol. This effect is mainly mediated by ER, although our findings do not exclude a participation of ER in the neuroprotective effects of the hormone. Moreover, results from the unlesioned animals support the beneficial role of estradiol pretreatment by increasing the activity of signaling pathways implicated in cell survival.
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Acknowledgements |
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Footnotes |
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M.D.A. and P.M. contributed equally to this work.
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, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol; 5-diol, 5-androsten-3, 17-diol; PI3K, phosphatidylinositol-3 kinase; Akt, protein kinase B; GSK3, glycogen synthase kinase 3; DOPAC, 3,4-dihydroxyphenylacetic acid; pAkt or pSer473Akt, phosphorylated protein kinase B at serine 473; pGSK3 or pSer9GSK3, phosphorylated glycogen synthase kinase 3 at serine 9; ANOVA, analysis of variance.
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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, p < 0.05 versus MPTP + 17
, p < 0.05 versus MPTP + PPT. Values are normalized to control values and represent the mean relative units (R.U.) ± S.E.M. of three mice per group. A representative example of the Western blots is shown. 
