Effects of estrogens on striatal damage after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in male and female mice
Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan. Molecular and Cellular Endocrinology
(Impact Factor: 4.41).
09/2008; 296(1-2):87-93. DOI: 10.1016/j.mce.2008.07.019
Emerging evidence shows a beneficial effect of estrogens for Parkinson's disease, yet the exact potency of these compounds implicated remain obscured. In this study, we investigated the neuroprotective effect of 17beta-estradiol and estrone against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal toxicity in mice. The neuroprotective effects of both compounds were evaluated by HPLC and Western blot analyses 5 days after the last of 4 consecutive injections of MPTP at 1-h intervals to mice. Subacute treatment (10 days) with estrone or 17beta-estradiol at low doses (0.05 and 0.2mg/kg) showed no significant changes against MPTP-induced damage of striatal dopamine terminals in mice. Furthermore, acute treatment with estrone at high doses (0.5 and 2.0mg/kg) showed no significant alterations against MPTP-induced damage of striatal dopamine terminals in mice. In contrast, acute treatment with 17beta-estradiol at high doses exhibited a neuroprotective effect against the damage of striatal dopamine terminals in both male and female mice after MPTP treatments. The results demonstrate that estrogen therapy with high doses may have a neuroprotective effect on the damage of striatal dopamine terminals in the MPTP-induced mice. These findings may lead to be development of estrogen therapy for the prevention and treatment of Parkinson's disease.
Available from: Hirohiko Kanai
- "The brains were quickly removed and frozen with dry ice powder. HPLC analysis of DA and its metabolites in the brain regions was performed as previously described (Ookubo et al., 2008, 2013). "
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ABSTRACT: Thyroid hormone receptors (TRs) are divided into two functional types: TRα and TRβ. TRs play pivotal roles in the developing brain, and disruption of TRs can produce permanent behavioural abnormality in animal models and in humans.
Here we examined behavioural changes, regional monoamine metabolism and expression of epigenetic modulatory proteins, including acetylated histone H3 (acH3) and histone deacetylase (HDAC), in the developing brain of TRα(-)disrupted (TRα(0/0)) and TRα-deficient (TRα(-/-)) mice. Tissue concentrations of dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT) and their metabolites in the mesocorticolimbic pathway were measured.
TRβ(-/-) mice, a model of attention(-)deficit/hyperactivity disorder (ADHD), showed significantly high exploratory activity and reduced habituation, whereas TRα(0/0) mice showed normal exploratory activity. The biochemical profiles of DA and 5-HT showed significantly low DA metabolic rates in the caudate putamen and nucleus accumbens and overall low 5-HT metabolic rates in TRβ(-/-) mice, but not in TRα(0/0) mice. Furthermore, the expression of acH3 was low in the dorsal raphe of TRβ(-/-) mice, and HDAC2/3 proteins were widely increased in the mesolimbic system.
These findings suggest that TRβ deficiency causes dysfunction of the monoaminergic system, accompanied by epigenetic disruption during the brain maturation process.
© The Author 2015. Published by Oxford University Press on behalf of CINP.
Available from: Therese Di Paolo
- "Timing of treatment with 17β-estradiol or estradiol benzoate seems to be critical to reach a maximal beneficial effect, with at least 24 h required for the pretreatment whereas shorter time intervals fail to achieve optimal protection (Gajjar et al., 2003). In support of this finding are data showing that treatment with a high dose of 17β-estradiol shortly prior to and after MPTP injection failed to protect striatal DA depletion whereas some effects were observed on DAT and tyrosine hydroxylase proteins levels (Ookubo et al., 2008). Moreover, in a study investigating several markers of dopaminergic function, the time required to obtain maximal protection against MA toxicity was observed with a 24-h pre-treatment of estradiol benzoate while pre-treatments of 30 min or 12 h showed incomplete and varying degrees of neuroprotection (Gajjar et al., 2003), suggesting different mechanisms of estradiol action (D'Astous et al., 2004a). "
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ABSTRACT: 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.
Available from: Mélanie Bourque
- "MPTP treatment was administered i.p. except for Ref.   (MPTP was injected s.c.). Mice were sacrificed 24 h after their last steroid injection except for Ã (sacrificed 3 days after MPTP treatment, Ref. ), for (sacrificed 5 days after MPTP treatment, Ref. ) and § (sacrificed the last day of steroid treatment, Ref.     "
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ABSTRACT: The sex difference in Parkinson's 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 Parkinson's 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.
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