Elyssa Berg

Introduction.  Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra.  The neuronal loss and dopamine depletion leads to Parkinson’s hallmark symptoms: bradykinesia, resting tremor, and muscle rigidity¹.  The existence of sex disparities in PD is well documented^2,3.  The prevalence is significantly higher in men compared to women with a male-to-female ratio of 1.6:1².  Women have a later age of onset and often express a milder PD phenotype³.  A number of studies show support of a neuroprotective role of estrogen in the development of PD⁴.  The neuroprotective effects are mediated through the activation of specific estrogen receptors, including ERα, ERβ and G protein-coupled estrogen receptor 1 (GPER1)^5,6.  These estrogen receptors show potential therapeutic targets^7,8.  Methods.  In three studies, the MPTP mouse model was used to simulate PD.  Male mice were randomized and treated with different combinations of 17β-estradiol, raloxifene (an estrogen modulator), G1 (GPER1 agonist), G15 (GPER1 antagonist), PPT (ERα agonist), DPN (ERβ agonist), and G1, as well as antagonists of ERα/β (ICI 182,780).  The resulting striata was analyzed through striatal dopamine assays, autoradiography, immunohistochemistry, and Western blots^5,6,7.  In another study, male rats were treated with the neurotoxin 6-OHDA to simulate PD.  The animals were randomized and treated with difference combinations of vehicle, 17β-estradiol, and estrogen receptor agonists (AC131, AC-186, AC-623, or AC-957).  The results were analyzed through immunohistochemistry and ELISA⁸.  Results.  G1 was shown to reproduce the effect of 17β-estradiol treatment in mice, while G15 blocked the effect of G1 and only partially blocked the effect of 17β-estradiol treatment in mice.  Mice treated with G15 were more susceptible to MPTP, while those treated with G1 were protected⁵.  The results suggest an important role of GPER1 in the neuroprotection of dopaminergic neurons.  Another study showed that ERα requires the activation of GPER1 to provide neuroprotection of dopaminergic neurons, while the neuroprotective effect of GPER1 is independent ERα/β⁶.  G15 opposed the protective effects of raloxifene, which suggests raloxifene modulates GPER1⁷. The ERβ agonist AC-186 was successful at preventing the loss of dopamine neurons in male rats⁸.  Conclusions.  These studies show the complex interplay between estrogen, estrogen receptors, and neuroprotection in the development of PD.  Since estrogen mediates its effects through estrogen receptors, ERα and ERβ, as well as GPER1, these serve as the basis for many new therapeutic interventions for PD^5-8.  Additional studies are needed for gonadal drug therapies to further these findings.

1. Benazzouz A, Mamad O, Abedi P, Bouali-Benazzouz R, Chetrit J. Involvement of dopamine loss in extrastriatal basal ganglia nuclei in the pathophysiology of Parkinson’s disease. Front Aging Neurosci. 2014;6. doi:10.3389/fnagi.2014.00087.
2. Lubomski M, Louise Rushworth R, Lee W, Bertram K, Williams D. Sex differences in Parkinson’s disease. Journal of Clinical Neuroscience. 2014;21(9):1503-1506. doi:10.1016/j.jocn.2013.12.016.
3. Gillies G, Pienaar I, Vohra S, Qamhawi Z. Sex differences in Parkinson’s disease. Front Neuroendocrinol. 2014;35(3):370-384. doi:10.1016/j.yfrne.2014.02.002.
4. Smith K, Dahodwala N. Sex differences in Parkinson’s disease and other movement disorders. Exp Neurol. 2014;259:44-56. doi:10.1016/j.expneurol.2014.03.010.
5. Bourque M, Morissette M, Côté M, Soulet D, Di Paolo T. Implication of GPER1 in neuroprotection in a mouse model of Parkinson’s disease. Neurobiol Aging. 2013;34(3):887-901. doi:10.1016/j.neurobiolaging.2012.05.022.
6. Bourque M, Morissette M, Di Paolo T. Neuroprotection in Parkinsonian-treated mice via estrogen receptor α activation requires G protein-coupled estrogen receptor 1. Neuropharmacology. 2015;95:343-352. doi:10.1016/j.neuropharm.2015.04.006.
7. Bourque M, Morissette M, Di Paolo T. 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. Neurobiol Aging. 2014;35(10):2347-2356. doi:10.1016/j.neurobiolaging.2014.03.017.
8. McFarland K, Price D, Davis C et al. AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson’s Disease Rat Model. ACS Chem Neurosci. 2013;4(9):1249-1255. doi:10.1021/cn400132u.