Estrogen attenuates the MPTP-induced loss of dopamine neurons from the mouse SNc despite a lack of estrogen receptors (ERα and ERβ)

Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
Experimental Neurology (Impact Factor: 4.7). 01/2005; 190(2):468-77. DOI: 10.1016/j.expneurol.2004.08.009
Source: PubMed


Estrogen attenuates the loss of dopamine from striatum and dopamine neurons from the substantia nigra (SNc) in animal models of Parkinson's disease. Interestingly, estrogen receptors (ERalpha and ERbeta) are thought to be sparse or absent in mouse striatum and SNc. Since ERalpha is markedly induced in rodent cortex after ischemic injury, the present studies evaluated changes in ERs after acute treatment with the dopamine neurotoxin MPTP. Mice were injected daily with estradiol, injected with MPTP on day 6, and brains collected on day 9 or 13. Immunocytochemistry was then used to assess tyrosine hydroxylase (TH) in striatum and investigate the localization of ERalpha and ERbeta in the striatum and SNc. In addition, cryostat sections were hybridized with a riboprobe complementary to ERalpha or ERbeta mRNA. Evaluation of TH immunoreactivity revealed a dense network of fibers in the striatum of vehicle-treated animals, while a near complete loss of terminals was seen after MPTP treatment. When, however, mice were pretreated with estradiol, the MPTP-induced loss of TH was attenuated. Evaluation of ERalpha and ERbeta in the SNc and striatum demonstrated a sparse localization of both ERs in vehicle-treated mice, a pattern that did not change in animals treated with vehicle/MPTP or estradiol/MPTP. These data demonstrate that ERs are sparse in the mouse striatum and SNc and show that this pattern does not change after MPTP intoxication. This observation and the finding that estrogen affords some protection against MPTP suggest that estrogen may act via nuclear receptor independent mechanisms to protect dopamine neurons from toxins such as MPTP.

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    • "In clinical studies, womenwho received estrogen replacement therapy soon after menopause were at lower risk of developing Parkinson's disease (Currie et al., 2004).Women who received short-term estrogen treatment had an increase in dopamine transporters in the caudate putamen (Gardiner et al., 2004). Multiple groups have shown that in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) animal model of Parkinson's disease, exogenous physiological levels of estradiol were able to protect against loss of DA neurons (Kenchappa et al., 2004; Ramirez et al., 2003; Shughrue, 2004). Others have shown that in Parkinson's disease animal model of 6- hydroxydopamine (6-OHDA), estradiol can also act indirectly by activating the insulin-like growth factor-1 (IGF-1) receptor to protect against 6-OHDA induced neuronal loss (Quesada and Micevych, 2004). "
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    ABSTRACT: Estetrol (E4) is a recently described natural estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. The aim of the present study was to define the importance of E4 in the attenuation of neonatal hypoxic-ischemic encephalopathy. Antioxidative effect of 650 μM, 3.25 mM and 6.5 mM E4 on primary hippocampal cell cultures was studied before/after H202-induced oxidative stress. To examine the oxidative stress and the cell viability, lactate dehydrogenase activity and cell proliferation colorimetric assays were performed. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal hypoxic-ischemic encephalopathy model of 7-day-old newborn rat pups was used. The neuroprotective and therapeutic effectst of estetrol before/after hypoxic-ischemic insult was studied in 1 mg/kg//day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day E4 pretreated/treated groups and compared with the sham and the vehicle treated groups. The body temperature of the rat pups was examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of microtubule-associated protein-2, doublecortin and vascular-endothelial growth factor were evaluated by histo- and immunohistochemistry. ELISAs were performed on blood samples to detect concentrations of S100B and glial fibrillary acidic protein as brain damage markers. This work reveals for the first time that E4 significantly decreases LDH activity and enhances cell proliferation in primary hippocampal neuronal cell cultures in vitro, and decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo.
    Experimental Neurology 11/2014; 261. DOI:10.1016/j.expneurol.2014.07.015 · 4.70 Impact Factor
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    • "Sex differences in the levels of ERs within the NSDA pathway could potentially underlie sex differences in estrogenic signalling pathways. Separate studies using the same antibody reported that ERb was absent in the male mouse SNc (Shughrue, 2004), but weakly expressed in the female SNc (Mitra et al., 2003; Merchenthaler et al., 2004); the striatum appears not to express ERb (Shughrue, 2004). ERa was not found in the DAergic neurons of the SNc and its expression in the striatum is low, although possibly at a higher level in female compared with male mice (Rodriguez- Navarro et al., 2008). "
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    ABSTRACT: Parkinson’s disease (PD) displays a greater prevalence and earlier age at onset in men. This review addresses the concept that sex differences in PD are determined, largely, by biological sex differences in the NSDA system which, in turn, arise from hormonal, genetic and environmental influences. Current therapies for PD rely on dopamine replacement strategies to treat symptoms, and there is an urgent, unmet need for disease modifying agents. As a significant degree of neuroprotection against the early stages of clinical or experimental PD is seen, respectively, in human and rodent females compared with males, a better understanding of brain sex dimorphisms in the intact and injured NSDA system will shed light on mechanisms which have the potential to delay, or even halt, the progression of PD. Available evidence suggests that sex-specific, hormone-based therapeutic agents hold particular promise for developing treatments with optimal efficacy in men and women.
    Frontiers in Neuroendocrinology 08/2014; 35(3). DOI:10.1016/j.yfrne.2014.02.002 · 7.04 Impact Factor
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    • "The greater effect of MPTP in male versus female mice on striatal dopamine concentrations is consistent with previous findings (Miller et al., 1998). This sex difference may be due to a protective estrogenic effect (Dluzen et al., 1996; Shughrue, 2004). "
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    ABSTRACT: Several investigations have reported that mice administered paraquat dichloride (PQ·Cl2) by intraperitoneal injection exhibit a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, male and female C57BL/6J mice were administered PQ·Cl2 in the diet at concentrations of 0 (control), 10, and 50 ppm for a duration of 13 weeks. A separate group of mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) during week 12 as positive controls to produce a loss of dopaminergic neurons in the SNpc. The comparative effects of PQ and MPTP on the SNpc and/or striatum were assessed using neurochemical, neuropathological, and stereological endpoints. Morphological and stereological assessments were performed by investigators 'blinded' to the origin of the tissue. Neither dose of PQ·Cl2 (10 ppm or 50 ppm in the diet) caused a loss of striatal dopamine or dopamine metabolite concentrations in the brains of mice. Pathological assessments of the SNpc and striatum showed no evidence of neuronal degeneration or astrocytic/microglial activation. Furthermore, the number of tyrosine hydroxylase-positive (TH+) neurons in the SNpc was not reduced in PQ-treated mice. In contrast, MPTP caused a decrease in striatal dopamine concentration, a reduction in TH+ neurons in the SNpc, and significant pathological changes including astrocytic and microglial activation in the striatum and SNpc. The MPTP-induced effects were greater in males than in females. It is concluded that 13 weeks of continuous dietary exposure of C57BL/6J mice to 50 ppm PQ·Cl2 (equivalent to 10.2 mg and 15.6 mg PQ ion/kg body weight/day for males and females, respectively) does not result in the loss of, or damage to, dopaminergic neurons in the SNpc.
    Regulatory Toxicology and Pharmacology 01/2014; 68(2). DOI:10.1016/j.yrtph.2013.12.010 · 2.03 Impact Factor
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