Estrogen attenuates the MPTP-induced loss of dopamine neurons from the mouse SNc despite a lack of estrogen receptors (ERα and ERβ)
Introduction
Parkinson's disease is a progressive neurodegenerative disease characterized by the selective loss of dopamine neurons from the substantia nigra (SNc) and a concomitant appearance of motor disturbances including tremors, rigidity, and a slowness of movement (akinesia). Parkinson's disease is a common disease seen throughout the world, with a prevalence of approximately 1%. While little difference in the frequency of Parkinson's disease has been noted among countries and cultures, a number of studies have indicated that the prevalence of Parkinson's disease is 1.36–3.7 times higher in men than in women (see Baldereschi et al., 2000, Bower et al., 1999, Bower et al., 2000, Diamond et al., 1990). Furthermore, several small studies have suggested that the use of estrogen replacement therapy can further reduce the risk of Parkinson's disease in postmenopausal women (Ascherio et al., 2003, Benedetti et al., 2001). Although preliminary, these data indicate that estrogen may play a protective role in Parkinson's disease.
In animal models of neurodegeneration, estrogen is a potent neuroprotective factor. The treatment of animals with estradiol is known to reduce the loss of neurons after ischemic injury, attenuating the loss of cortical (Dubal et al., 1998, Dubal et al., 2001, Rusa et al., 1999, Simpkins et al., 1997) and hippocampal neurons (Jover et al., 2002, Shughrue et al., 2002, Sudo et al., 1997) after focal or global ischemia. Estrogen has also been shown to attenuate the loss of neurons in models of traumatic brain injury (Roof and Hall, 2000) and prevent the loss of septal cholinergic neurons after fimbria–fornix lesion (Rabbani et al., 1997). While the exact mechanism by which estrogen protects these neurons is unclear, a number of observations have suggested a role for nuclear estrogen receptors (ERα and/or ERβ). Early studies in rats revealed that ERα was dramatically up-regulated throughout the injured cerebral cortex after ischemia while levels remained low on the contralateral side (Dubal et al., 1999, Merchenthaler et al., 2004). Subsequent studies in estrogen receptor knockout mice (ERαKO and ERβKO) further revealed that ERα, but not ERβ, was required for estradiol to abate the loss of cortical neurons after an ischemic event (Dubal et al., 2001). In the gerbil, ERs have been detected in the CA1 pyramidal neurons of hippocampus, the neurons lost after global ischemia in ovariectomized animals (Shughrue and Merchenthaler, 2003). However, in contrast with the rodent cortex, the ERs seen in the gerbil hippocampus are naturally present and not modulated after ischemia. Taken together, these findings suggest that estrogen protects neurons after ischemia via a receptor-mediated mechanism, using ERs that are normally expressed or rapidly up-regulated after injury.
Studies in rodents have also shown that estrogen can reduce the loss of dopamine neurons in several models of Parkinson's disease (see Dluzen and Horstink, 2003). In the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model, 17β-estradiol reduced the loss of dopamine from the male and female striatum (Dluzen et al., 1996, Grandbois et al., 2000) and dopamine neurons from the SNc (Callier et al., 2001). Furthermore, the treatment of mice with the ER antagonist tamoxifen inhibited the efficacy of 17β-estradiol (Dluzen et al., 2001), an indication that estradiol may act through ERα and/or ERβ to prevent the loss of nigrostriatal dopamine neurons. Interestingly, studies have shown that both the number and distribution of ERs (ERα and ERβ) are sparse or absent in the mouse striatum and SNc (Koch and Ehret, 1989, Merchenthaler et al., 2003, Shughrue et al., 1997a, Shughrue et al., 1997b, Stumpf and Sar, 1975). Based on these observations and the finding that ERα is markedly induced in rodent cortex after ischemic injury (Dubal et al., 1999, Merchenthaler et al., 2004), the present studies evaluated changes in ERs in the mouse striatum and SNc after acute treatment with the dopamine neurotoxin MPTP.
Section snippets
Animals and tissue collection
Castrated male mice (C57/blk6; Taconic, Germantown, NY) were housed in the animal care facility (AAALAC certified) with a 12:12-h light–dark photoperiod and free access to tap water and rodent chow. After acclimation, animals (n = 8/group) were injected subcutaneously daily with corn oil or 100 μg of 17β-estradiol until euthanasia. Six days after the start of estrogen treatment, mice also received four subcutaneous injections of normal saline or 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine
Estrogen abates the loss of TH immunoreactivity in the mouse striatum
A number of studies have shown that estrogen attenuates the loss of dopamine from the mouse striatum after treatment with the dopamine neurotoxin MPTP. In an attempt to ascertain the efficacy of estrogen in our mouse model of Parkinson's disease, animals were treated daily with estradiol throughout the study, injected with MPTP (4 × 20 mpk) on day 6, and then allowed to survive for an additional 3 or 7 days. After euthanasia, the dopamine terminals in the striatum were visualized with
Discussion
The present studies used a mouse model of Parkinson's disease to show that estradiol can attenuate the loss of striatal dopamine terminals after treatment with the dopamine neurotoxin MPTP. Subsequent studies evaluated the localization of ERs in the nigrostriatal system, an attempt to ascertain the mechanism of estrogen action. Interestingly, the results of immunocytochemical and in situ hybridization studies revealed that ERs (ERα and ERβ) are sparse or absent in both the striatum and SNc of
Acknowledgments
I thank Amy Vanko and Brian West for their excellent technical assistance with the dosing of mice with compound and MPTP.
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