Effect of estrogen receptor agonists treatment in MPTP mice: Evidence of neuroprotection by an ERα agonist

Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL, 2705 Laurier Boulevard, Quebec City, Que. G1V 4G2, Canada.
Neuropharmacology (Impact Factor: 5.11). 01/2005; 47(8):1180-8. DOI: 10.1016/j.neuropharm.2004.08.020
Source: PubMed


Beneficial effects of 17 beta-estradiol (17 beta-E(2)) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion are well documented but the mechanisms implicated are poorly understood. The present experiments investigated the effect of estrogen receptor (ER) agonists treatment in MPTP mice as compared to 17 beta-E(2). The agonists specific for each subtype were 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol (PPT) (ER alpha agonist), 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) and Delta 3-diol (5-androsten-3 beta, 17 beta-diol, also known as 5-androstenediol, androstenediol or hermaphrodiol) (ER beta agonists). Biogenic amines were assayed by HPLC with electrochemical detection. 8 mg/kg of MPTP was administered to give a moderate depletion of striatal DA and its metabolite dihydroxyphenylacetic acid (DOPAC). Protection against MPTP-induced striatal DA and DOPAC depletion was obtained with PPT and 17 beta-E(2) but not with DPN or Delta 3-diol. The striatal dopamine transporter (DAT) was assayed by autoradiography with [(125)I]RTI-121-specific binding. A positive and significant correlation was observed between striatal DA concentrations and [(125)I]RTI-121-specific binding, suggesting that estrogenic treatment that prevented the MPTP-induced DA depletion also prevented loss of DAT. The effect of PPT suggests the implication of an ER alpha in the estrogenic neuroprotection against MPTP. Pointing out which ER is implicated in neuroprotection becomes helpful in designing more specific estrogenic drugs for protection of the aging brain.

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    • "The left anterior striata were dissected, homogenized in 250 ml of 0.1 N HClO 4 at 4 C and then centrifuged at 10,000  g for 10 min (4 C) to precipitate proteins. The concentrations of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by high performance liquid chromatography (HPLC) with electrochemical detection (D'Astous et al., 2004). 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 mm, 3.9 mm  150 cm), a BAS LC-4C electrochemical detector and a glassy carbon electrode. "
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    ABSTRACT: We have previously shown that estrogen receptors (ER) α activation and G protein-coupled estrogen receptor 1 (GPER1) stimulation reproduce 17β-estradiol protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced toxicity of dopamine neurons in mice. This suggests that both ERα and GPER1 have a major role in mediating protection of dopamine neurons, but also suggests a potential collaboration between these receptors. The present study tested the hypothesis of a potential collaboration between ER a/β and GPER1 in neuroprotection of dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated male mice, using a pharmacologic approach. The ERα/β antagonist, ICI 182,780, blocked the protective effects of 17β-estradiol, but not those of GPER1 agonist G1, on dopamine concentration as well as dopamine transporter and vesicular monoamine transporter 2 specific binding in both the striatum and the substantia nigra. G1 protection was accompanied by an increase in Blc-2 and brain-derived neurotrophic factor (BDNF) levels in the striatum; coadministration of ICI 182,780 blocked the effect of G1 only on BDNF levels. ERα activation by its agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) protected dopamine neurons, an effect associated with activation of striatal Akt signaling and an increase in Bcl-2 and BDNF levels; the GPER1 antagonist G15 inhibited the decrease in glycogen synthase kinase 3β activity and the increase in BDNF induced by PPT. Our results suggest that ERα requires GPER1 in protection of dopamine neurons and modulation of signaling pathways, and that the effect of GPER1 occurs independently of ERα/β, whereas GPER1 require ERα/β to increase BDNF levels. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 04/2015; 95. DOI:10.1016/j.neuropharm.2015.04.006 · 5.11 Impact Factor
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    • "C) to precipitate proteins. The concentrations of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by high performance liquid chromatography with electrochemical detection (D'Astous et al., 2004 "
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    ABSTRACT: 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.
    Neurobiology of aging 03/2014; 35(10). DOI:10.1016/j.neurobiolaging.2014.03.017 · 5.01 Impact Factor
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    • "An extensive literature, both epidemiological and experimental, suggests that males are more vulnerable to trauma and neurodegenerative events/diseases (de Lau and Breteler 2006; Van Den Eeden et al. 2003; Coronado et al. 2011; Mehal et al. 2013). The lower vulnerability of females may be related to the documented neuroprotective role of estrogen in trauma and neurodegenerative studies (Yune et al. 2008; Rau et al. 2003; Roof and Hall 2000; D'Astous et al. 2004; Hoffman et al. 2006; Tang et al. 1996), although recent work emphasizes that sex as an injury variable includes more than single hormone-single receptor interactions, and involves both genomic and nongenomic effects (Cheng and Hurn 2010; Herson et al. 2009). Although a preponderance of evidence suggests that some component of estrogen-mediated protection derives from down-regulation of dopamine transporter function in the striatum (Wallace et al. 2006; Disshon and Dluzen 1999; Murray et al. 2003), other mechanisms are likely involved in striatum and elsewhere, including expression of endogenous anti-oxidants such as paraoxonase 2 (Giordano et al. 2013) and glutathione (Kumar et al. 2011), as well as anti-oxidant enzyme systems (Kumar et al. 2011; Rao et al. 2011). "
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    ABSTRACT: HIV-associated damage to the central nervous system results in cognitive and motor deficits. Anti-retroviral therapies reduce the severity of symptoms, yet the proportion of patients affected has remained the same or increased. Although approximately half of HIV-infected patients worldwide are women, the question of whether biological sex influences outcomes of HIV infection has received little attention. We explored this question for both behavioral and cellular/morphologic endpoints, using a transgenic mouse that inducibly expresses HIV-1 Tat in the brain. After 3 months of HIV-1 Tat exposure, both sexes showed similar reduced open field ambulation. Male Tat+ mice also showed reduced forelimb grip strength and enhanced anxiety in a light–dark box assay. Tat+ males did not improve over 12 weeks of repeated rotarod testing, indicating a motor memory deficit. Male mice also had more cellular deficits in the striatum. Neither sex showed a change in volume or total neuron numbers. Both had equally reduced oligodendroglial populations and equivalent microglial increases. However, astrogliosis and microglial nitrosative stress were higher in males. Dendrites on medium spiny neurons in male Tat+ mice had fewer spines, and levels of excitatory and inhibitory pre- and post-synaptic proteins were disrupted. Our results predict sex as a determinant of HIV effects in brain. Increased behavioral deficits in males correlated with glial activation and synaptic damage, both of which are implicated in cognitive/motor impairments in patients. Tat produced by residually infected cells despite antiretroviral therapy may be an important determinant of the synaptodendritic instability and behavioral deficits accompanying chronic infection. Electronic supplementary material The online version of this article (doi:10.1007/s00429-013-0676-6) contains supplementary material, which is available to authorized users.
    Brain Structure and Function 12/2013; 220(2). DOI:10.1007/s00429-013-0676-6 · 5.62 Impact Factor
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