The Role of Estrogen and Estrogen Receptors in the Development of Parkinson’s Disease and Their Potential as Therapeutic Interventions
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 documented2,3. 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 targets7,8. 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 blots5,6,7. 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 PD5-8. Additional studies are needed for gonadal drug therapies to further these findings.
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