Molecular Endocrinology and Genomic Research Center

Québec, Canada

Molecular Endocrinology and Genomic Research Center

Québec, Canada
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Bourque M.,Molecular Endocrinology and Genomic Research Center | Bourque M.,Laval University | Paolo T.D.,Molecular Endocrinology and Genomic Research Center | Paolo T.D.,Laval University
Frontiers in Endocrinology | Year: 2011

The existence of a sex difference in Parkinson's disease (PD) is observed as related to several variables, including susceptibility of the disease, age at onset, and symptoms. These differences between men and women represent a significant characteristic of PD, which suggest that estrogens may exert beneficial effects against the development and the progression of the disease. This paper reviews the neuroprotective and neuromodulator effects of 17β-estradiol and progesterone as compared to androgens in the nigrostriatal dopaminergic (NSDA) system of both female and male rodents. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD and methamphetamine toxicity faithfully reproduce the sex differences of PD in that endogenous estrogen levels appear to influence the vulnerability to toxins targeting the NSDA system. Exogenous 17β-estradiol and/or progesterone treatments show neuroprotective properties against NSDA toxins while androgens fail to induce any beneficial effect. Sex steroid treatments show male and female differences in their neuroprotective action against methamphetamine toxicity. NSDA structure and function, as well as the distribution of estrogen receptors, show sex differences and may influence the susceptibility to the toxins and the response to sex steroids. Genomic and non-genomic actions of 17β-estradiol converge to promote survival factors and the presence of both estrogen receptors α and β are critical to 17β-estradiol neuroprotective action against MPTP toxicity. © 2011 Bourque, Dluzenand DiPaolo.


Bourque M.,Molecular Endocrinology and Genomic Research Center | Bourque M.,Laval University | Di Paolo T.,Molecular Endocrinology and Genomic Research Center | Di Paolo T.,Laval University
Psychoneuroendocrinology | Year: 2011

Male mice were reported to display greater methamphetamine-induced neurotoxicity than females. The present study evaluated the involvement of phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK1/2) pathways in this sex-dependent methamphetamine toxicity. Intact female and male mice were administered methamphetamine (20 or 40 mg/kg) and euthanized a week later. Dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) autoradiography in the lateral striatum showed a greater sensitivity in male mice treated with 20 mg/kg methamphetamine compared to female mice. Striatal dopamine concentration and DAT autoradiography showed a more extensive depletion in male mice given 40 mg/kg methamphetamine compared to female mice. Mice administered 40 mg/kg methamphetamine showed no sex difference in striatal VMAT2 autoradiography. In the substantia nigra, DAT specific binding was decreased only in male mice treated with 40 mg/kg methamphetamine and DAT mRNA levels decreased in methamphetamine-treated female and male mice. Methamphetamine-treated male mice presented a dose-dependent decrease of VMAT2 mRNA levels. Methamphetamine reduced insulin-like growth factor 1 receptor levels in females at both methamphetamine doses tested whereas it elevated G protein-coupled estrogen receptor 1 (GPER1) only in male mice. Phosphorylated Akt levels decreased only in male mice treated with 40 mg/kg methamphetamine. Glycogen synthase kinase 3β levels were reduced in male mice at both methamphetamine doses tested and in females receiving 40 mg/kg. Bcl-2 levels were increased in male mice treated with methamphetamine, whereas ERK1/2 and BAD levels were unchanged. These results implicate some of the signaling pathways associated with the sex differences in methamphetamine-induced toxicity. © 2011 Elsevier Ltd.


Al Sweidi S.,Molecular Endocrinology and Genomic Research Center | Al Sweidi S.,Laval University | Sanchez M.G.,Molecular Endocrinology and Genomic Research Center | Sanchez M.G.,Laval University | And 5 more authors.
Journal of Neuroendocrinology | Year: 2012

Parkinson's disease (PD) is an age-related neurodegenerative disorder with a higher incidence in the male population. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, 17β-oestradiol but not androgens were shown to protect dopamine (DA) neurones. We report that oestrogen receptors (ER)α and β distinctly contribute to neuroprotection against MPTP toxicity, as revealed by examining the membrane DA transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hyroxylase in ER wild-type (WT) and knockout (ERKO) C57Bl/6 male mice. Intact ERKOβ mice had lower levels of striatal DAT and VMAT2, whereas ERKOα mice were the most sensitive to MPTP toxicity compared to WT and ERKOβ mice and had the highest levels of plasma androgens. In both ERKO mice groups, treatment with 17β-oestradiol did not provide neuroprotection against MPTP, despite elevated plasma 17β-oestradiol levels. Next, the recently described membrane G protein-coupled oestrogen receptor (GPER1) was examined in female Macaca fascicularis monkeys and mice. GPER1 levels were increased in the caudate nucleus and the putamen of MPTP-monkeys and in the male mouse striatum lesioned with methamphetamine or MPTP. Moreover, neuroprotective mechanisms in response to oestrogens transmit via Akt/glycogen synthase kinase-3 (GSK3) signalling. The intact and lesioned striata of 17β-oestradiol treated monkeys, similar to that of mice, had increased levels of pAkt (Ser 473)/βIII-tubulin, pGSK3 (Ser 9)/βIII-tubulin and Akt/βIII-tubulin. Hence, ERα, ERβ and GPER1 activation by oestrogens is imperative in the modulation of ER signalling and serves as a basis for evaluating nigrostriatal neuroprotection. © 2011 Blackwell Publishing Ltd.


Gregoire L.,Molecular Endocrinology and Genomic Research Center | Jourdain V.A.,Molecular Endocrinology and Genomic Research Center | Jourdain V.A.,Laval University | Townsend M.,EMD Serono, Inc. | And 3 more authors.
Parkinsonism and Related Disorders | Year: 2013

Introduction: Safinamide is a compound under investigation for use in the treatment of Parkinson's disease for combination with pharmacological therapy currently available. The objective of this study was to test the effects of safinamide in an animal model of l-DOPA-induced dyskinesias (LID), the MPTP lesioned dyskinetic macaque monkey, in comparison to and in combination with amantadine. Methods: LID and parkinsonian symptoms were measured in dyskinetic monkeys treated with l-DOPA with and without several dose levels of safinamide, amantadine, and the two in combination. Safinamide plasma levels were monitored during the experiments. Results: Safinamide pre-treatment (3, 10, 20 and 30 mg/kg) dose-dependently reduced LID scores, in two acute and one semi-chronic experiment. Intensity and duration of LID were reduced and inversely correlated with safinamide blood levels. All doses of safinamide tested prolonged the duration of the beneficial antiparkinsonian effect of l-DOPA. Amantadine (5 and 20 mg/kg) reduced LID, but reduced duration of antiparkinsonian response to l-DOPA. When added to amantadine (5 mg/kg), safinamide showed no (3 mg/kg) or modest (20 mg/kg) additional beneficial effects on LID while the combined treatment prevented the reduction of the duration of the l-DOPA antiparkinsonian effect observed with amantadine only. Conclusions: Safinamide and amantadine reduced LID in this primate model while only safinamide increased the duration of the antiparkinsonian response of l-DOPA, suggesting that safinamide may have effects on LID that are pharmacologically distinct from amantadine, which is in current clinical use for control of LID. © 2013 Elsevier Ltd.


Bourque M.,Molecular Endocrinology and Genomic Research Center | Bourque M.,Laval University | Morissette M.,Molecular Endocrinology and Genomic Research Center | Cote M.,Laval University | And 3 more authors.
Neurobiology of Aging | Year: 2013

This study investigated the contribution of the new G protein-coupled estrogen receptor 1 (GPER1) in neuroprotection by 17β-estradiol in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. In intact mice, administration of GPER1 agonist G1 reproduced the effect of 17β-estradiol in increasing striatal dopamine metabolite concentrations as well as the turnover of dopamine. GPER1 antagonist G15 blocked the effect of G1 on homovanillic acid/dopamine ratio and partially for 17β-estradiol. MPTP mice treated with G15 were more susceptible to MPTP toxicity with a greater decrease in striatal dopamine concentration and dopamine transporter specific binding. In MPTP mice, dopamine concentrations as well as dopamine and vesicular monoamine transporter 2 specific binding showed that G1 treatment was as potent as 17β-estradiol in protecting striatum and substantia nigra. G15 antagonized completely the neuroprotective effects of G1 in the striatum and substantia nigra as well as protection by 17β-estradiol in the striatum but partially in the substantia nigra. This study showed an important role of GPER1 in neuroprotection and that G1 is as potent as 17β-estradiol in mediating beneficial effects. © 2013 Elsevier Inc.


PubMed | Molecular Endocrinology and Genomic Research Center
Type: Comparative Study | Journal: Neuropharmacology | Year: 2012

Methamphetamine induces a greater neurodegenerative effect in male versus female mice. In order to investigate this sex difference we studied the involvement of Akt and extracellular signal-regulated kinase (ERK1/2) in methamphetamine toxicity as a function of time post-treatment (30 min, 1 and 3 days). Methamphetamine-induced decreases in dopamine concentrations and dopamine transporter (DAT) specific binding in the medial striatum were similar in female and male mice when evaluated 1 day post-methamphetamine (40 mg/kg). At 3 days post-methamphetamine, striatal dopamine concentration and DAT specific binding continued to decline in males, whereas females showed a recovery with increases in dopamine content and DAT specific binding in medial striatum at day 3 versus day 1 post-methamphetamine. The reduction in striatal vesicular monoamine transporter 2 specific binding observed at 1 and 3 days post-methamphetamine showed neither a sex- nor temporal-dependent effect. Under the present experimental conditions, methamphetamine treatments had modest effects on dopamine markers measured in the substantia nigra. Proteins assessed by Western blots showed similar reductions in both female and male mice for DAT proteins at 1 and 3 days post-methamphetamine. An increase in the phosphorylation of striatal Akt (after 1 day), glycogen synthase kinase 3 (at 1 and 3 days) and ERK1/2 (30 min post-methamphetamine) was only observed in females. Striatal glial fibrillary acidic protein levels were augmented in both females and males at 3 days post-methamphetamine. These results reveal some of the sex- and temporally-dependent effects of methamphetamine toxicity on dopaminergic markers and suggest some of the signaling pathways associated with these responses.


PubMed | Molecular Endocrinology and Genomic Research Center
Type: Journal Article | Journal: Frontiers in neuroendocrinology | Year: 2012

Studies with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinsons disease have shown the ability of 17-estradiol to protect the nigrostriatal dopaminergic system. This paper reviews the signaling pathways mediating the neuroprotective effect of 17-estradiol against MPTP-induced toxicity. The mechanisms of 17-estradiol action implicate activation of signaling pathways such as the phosphatidylinositol-3 kinase/Akt and the mitogen-activated protein kinase pathways. 17-estradiol signaling is complex and integrates multiple interactions with signaling molecules that act to potentiate a protective effect. 17-estradiol signaling is mediated via estrogen receptors, including GPER1, but others receptors, such as the IGF-1 receptor, are implicated in the neuroprotective effect. Glial and neuronal crosstalk is a critical factor in the maintenance of dopamine neuronal survival and in the neuroprotective action of 17-estradiol. Compounds that stimulate GPER1 such as selective estrogen receptor modulators and phytoestrogens show neuroprotective activity and are alternatives to 17-estradiol.


PubMed | Molecular Endocrinology and Genomic Research Center
Type: Journal Article | Journal: Journal of neurosurgery | Year: 2013

Subthalamotomy is a stereotactic surgery performed in patients with disabling dyskinesias due to Parkinson disease. The authors set out to model this human condition in MPTP monkeys and determine if subthalamotomy allowed a reduction of levodopa for similar benefit.The authors performed unilateral subthalamotomy in 4 parkinsonian dyskinetic monkeys by stereotactic injection of ibotenic acid. An optimal dose, defined as the highest dose of levodopa improving parkinsonian motor symptoms while inducing low or no dyskinesias, was established in these animals. Each monkey was scored for the antiparkinsonian and dyskinetic effects of the optimal dose of levodopa, as well as suboptimal and dyskinesia-inducing doses (60% and 140% of the optimal dose, respectively), and these scores were compared with those obtained at baseline before and after subthalamotomy. Bradykinesia was assessed by a prehension task.Unilateral subthalamotomy had a positive effect on the antiparkinsonian response for all doses of levodopa as well as the baseline. There were no differences in the antiparkinsonian response between the suboptimal dose postsurgery and the optimal dose presurgery. Dyskinesias were increased at the suboptimal and the optimal doses. After surgery, the duration of response to levodopa increased between 20% and 25% in the suboptimal dose, whereas it remained unchanged with higher doses. Bradykinesia was significantly reduced after surgery only at the suboptimal dose.Subthalamotomy potentiated the response to suboptimal doses of levodopa. Thus, levodopa can be reduced by 40% after surgery for similar beneficial antiparkinsonian response and less dyskinesia than with an optimal dose before surgery.


PubMed | Molecular Endocrinology and Genomic Research Center
Type: Journal Article | Journal: Neurobiology of aging | Year: 2012

This study investigated the contribution of the new G protein-coupled estrogen receptor 1 (GPER1) in neuroprotection by 17-estradiol in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinsons disease. In intact mice, administration of GPER1 agonist G1 reproduced the effect of 17-estradiol in increasing striatal dopamine metabolite concentrations as well as the turnover of dopamine. GPER1 antagonist G15 blocked the effect of G1 on homovanillic acid/dopamine ratio and partially for 17-estradiol. MPTP mice treated with G15 were more susceptible to MPTP toxicity with a greater decrease in striatal dopamine concentration and dopamine transporter specific binding. In MPTP mice, dopamine concentrations as well as dopamine and vesicular monoamine transporter 2 specific binding showed that G1 treatment was as potent as 17-estradiol in protecting striatum and substantia nigra. G15 antagonized completely the neuroprotective effects of G1 in the striatum and substantia nigra as well as protection by 17-estradiol in the striatum but partially in the substantia nigra. This study showed an important role of GPER1 in neuroprotection and that G1 is as potent as 17-estradiol in mediating beneficial effects.


PubMed | Molecular Endocrinology and Genomic Research Center
Type: | Journal: Frontiers in endocrinology | Year: 2012

The existence of a sex difference in Parkinsons disease (PD) is observed as related to several variables, including susceptibility of the disease, age at onset, and symptoms. These differences between men and women represent a significant characteristic of PD, which suggest that estrogens may exert beneficial effects against the development and the progression of the disease. This paper reviews the neuroprotective and neuromodulator effects of 17-estradiol and progesterone as compared to androgens in the nigrostriatal dopaminergic (NSDA) system of both female and male rodents. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD and methamphetamine toxicity faithfully reproduce the sex differences of PD in that endogenous estrogen levels appear to influence the vulnerability to toxins targeting the NSDA system. Exogenous 17-estradiol and/or progesterone treatments show neuroprotective properties against NSDA toxins while androgens fail to induce any beneficial effect. Sex steroid treatments show male and female differences in their neuroprotective action against methamphetamine toxicity. NSDA structure and function, as well as the distribution of estrogen receptors, show sex differences and may influence the susceptibility to the toxins and the response to sex steroids. Genomic and non-genomic actions of 17-estradiol converge to promote survival factors and the presence of both estrogen receptors and are critical to 17-estradiol neuroprotective action against MPTP toxicity.

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