Mélanie Bourque

Neuroprotective actions of sex steroids in Parkinson's disease

The sex difference in Parkinsons disease, with a higher susceptibility in men, suggests a modulatory effect of sex steroids in the brain. Numerous studies highlight that sex steroids have neuroprotective properties against various brain injuries. This paper reviews the protective effects of sex hormones, particularly estradiol, progesterone and androgens, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinsons disease as compared to methamphetamine toxicity. The molecular mechanisms underlying beneficial actions of sex steroids on the brain have been investigated showing steroid, dose, timing and duration specificities and presently focus is on the dopamine signaling pathways, the next frontier. Both genomic and non-genomic actions of estrogen converge to promote survival factors and show sex differences. Neuroprotection by estrogen involves activation of signaling molecules such as the phosphatidylinositol-3 kinase/Akt and the mitogen-activated protein kinase pathways. Interaction with growth factors, such as insulin-like growth factor 1, also contributes to protective actions of estrogen.

Steroids-Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders: Steroids-Dopamine Interactions in CNS Disorders

Introduction: Dopamine cell loss is well documented in Parkinsons disease and dopamine hypofunction is proposed in certain depressive states. At the opposite, dopamine hyperactivity is an enduring theory in schizophrenia with extensive supporting evidence. Aims: This article reviews the sex differences in these diseases that are the object of many studies and meta‐analyses and could be explained by genetic differences but also an effect of steroids in the brain. This article then focuses on the extensive literature reporting on the effect of estrogens in these diseases and effects of the other ovarian hormone progesterone as well as androgens that are less documented. Moreover, dehydroepiandrosterone, the precursor of estrogens and androgens, shows effects on brain dopamine neurotransmission that are reviewed. To investigate the mechanisms implicated in the human findings, animal studies are reviewed showing effects of estrogens, progesterone, and androgens on various markers of dopamine neurotransmission under intact as well as lesioned conditions. Discussion: For possible future avenues for hormonal treatments in these central nervous system diseases, we discuss the effects of selective estrogen receptor modulators (SERMs), the various estrogen receptors and their specific drugs as well as progesterone drugs. Conclusion: Clinical and experimental evidence supports a role of steroid–dopamine interactions in the pathophysiology of schizophrenia, depression and Parkinsons disease. Specific steroidal receptor agonists and SERMs are available for endocrine and cancer treatments and could find other applications as adjunct treatments in central nervous system diseases.

Oestrogen Receptors and Signalling Pathways: Implications for Neuroprotective Effects of Sex Steroids in Parkinson's Disease

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.

Signaling pathways mediating the neuroprotective effects of sex steroids and SERMs in Parkinson's disease.

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

Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice

Raloxifene, used in the clinic, is reported to protect brain dopaminergic neurons in mice. Raloxifene was shown to mediate an effect through the G protein-coupled estrogen receptor 1 (GPER1). We investigated if raloxifene neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice is mediated through GPER1 by using its antagonist G15. Striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid to dopamine ratio as well as dopamine transporter and vesicular monoamine transporter 2 showed that raloxifene neuroprotection of dopaminergic neurons was blocked by G15. Protection by raloxifene was accompanied by activation of striatal Akt signaling (but not ERK1/2 signaling) and increased Bcl-2 and brain-derived neurotrophic factor levels; these effects were abolished by coadministration with G15. The effect of raloxifene was not mediated through increased levels of 17β-estradiol. MPTP mice had decreased plasma testosterone, dihydrotestosterone, and 3β-diol levels; this was prevented in raloxifene-treated MPTP mice. Our results suggest that raloxifene acted through GPER1 to mediate Akt activation, increase Bcl-2 and brain-derived neurotrophic factor levels, and protection of dopaminergic neurons and plasma androgens.

Implication of GPER1 in neuroprotection in a mouse model of Parkinson's disease.

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 Parkinsons 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.

Sex differences in methamphetamine toxicity in mice: Effect on brain dopamine signaling pathways

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 40mg/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 20mg/kg methamphetamine compared to female mice. Striatal dopamine concentration and DAT autoradiography showed a more extensive depletion in male mice given 40mg/kg methamphetamine compared to female mice. Mice administered 40mg/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 40mg/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 40mg/kg methamphetamine. Glycogen synthase kinase 3β levels were reduced in male mice at both methamphetamine doses tested and in females receiving 40mg/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.

Estrogen receptors and gonadal steroids in vulnerability and protection of dopamine neurons in a mouse model of Parkinson’s disease

17β-estradiol is well known to have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We investigated the neuroprotective contribution of estrogen receptors (ERα and ERβ) against MPTP toxicity by examining the membrane dopamine (DA) transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hydroxylase (TH) in ER knock out (ERKO) C57Bl/6 male mice compared to their plasma steroid levels. A dose-response to MPTP comparing wild-type (WT) to ERKO mice was studied. WT mice were also compared to ERKO mice pretreated with 17β-estradiol alone and with MPTP. Specific radioligand binding autoradiography and in situ hybridization for DAT, VMAT2 and TH were assayed in the striatum and the substantia nigra (SN). Intact ERKOβ mice had both striatal transporters levels lower than WT and ERKOα mice. MPTP caused a dose-dependent loss of both striatal transporters that correlated with striatal DA concentrations. Compared to WT and ERKOβ mice, ERKOα mice DAT, VMAT2 and TH were affected at lower MPTP doses. In the striatum and SN, ERKOα mice were more vulnerable and 17β-estradiol protected against MPTP toxicity only in WT mice. ERKOα mice blood plasma had higher levels of testosterone, dihydrotestosterone and 3β-diol compared to the plasma of WT and ERKOβ mice. 17β-estradiol treatment increased estradiol plasma levels in all genotypes. Striatal DA concentrations and SN TH mRNA correlated inversely with plasma testosterone and 3β-diol levels. Hence, in male mice the lack of ERα or ERβ altered their basal plasma steroid levels and both striatal DA transporters as well as their susceptibility to MPTP toxicity.

Male/Female Differences in Neuroprotection and Neuromodulation of Brain Dopamine

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.

Sex and temporally-dependent effects of methamphetamine toxicity on dopamine markers and signaling pathways

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 3β (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.