Differential contribution of estrogen receptors to the intestinal therapeutic effects of 17ß-estradiol in a murine model of Parkinson's disease.

Beneficial effects of estrogens have been reported in Parkinson's disease (PD) for many years. We previously reported their neuroprotective and anti-inflammatory potentials in the enteric nervous system of the intestine, a region possibly affected during the early stages of the disease according to Braak's hypothesis. Three different estrogen receptors have been characterized to date: the estrogen receptor alpha (ERα), the estrogen receptor beta (ERß) and the G protein coupled estrogen receptor 1 (GPER1). The aim of the present study was to decipher the individual contribution of each estrogen receptor to the therapeutic properties of 17ß-estradiol (E2) in the myenteric plexus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Different agonists, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT; ERα), 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; ERß), G1 (GPER1), and antagonists, ICI 182,780 (ERα and ERß), G15 (GPER1), were used to analyze the involvement of each receptor. We confirmed that G1 protects dopamine (DA) neurons to a similar extent as E2. An anti-inflammatory effect on proinflammatory macrophages and cultured human monocytes was also demonstrated with E2 and G1. The effects of PPT and DPN were less potent than G1 with only a partial neuroprotection of DA neurons by PPT and a partial reduction of interleukin (IL)- 1ß production in monocytes by PPT and DPN. Overall, the present results indicate that the positive outcomes of estrogens are mainly through activation of GPER1. Therefore, this suggests that targeting GPER1 could be a promising approach for future estrogen-based hormone therapies during early PD.

Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson's Disease Models.

Gastrointestinal disorders in Parkinson's disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.

Neuroprotection and immunomodulation of progesterone in the gut of a mouse model of Parkinson's disease.

Gastrointestinal symptoms appear in Parkinson's disease patients many years before motor symptoms, suggesting the implication of dopaminergic neurones of the gut myenteric plexus. Inflammation is also known to be increased in PD. We previously reported neuroprotection with progesterone in the brain of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and hypothesised that it also has neuroprotective and immunomodulatory activities in the gut. To test this hypothesis, we investigated progesterone administered to adult male C57BL/6 mice for 10 days and treated with MPTP on day 5. In an additional experiment, progesterone was administered for 5 days following MPTP treatment. Ilea were collected on day 10 of treatment and microdissected to isolate the myenteric plexus. Dopaminergic neurones were reduced by approximately 60% and pro-inflammatory macrophages were increased by approximately 50% in MPTP mice compared to intact controls. These changes were completely prevented by progesterone administered before and after MPTP treatment and were normalised by 8 mg kg-1 progesterone administered after MPTP. In the brain of MPTP mice, brain-derived neurotrophic peptide (BDNF) and glial fibrillary acidic protein (GFAP) were associated with progesterone neuroprotection. In the myenteric plexus, increased BDNF levels compared to controls were measured in MPTP mice treated with 8 mg kg-1 progesterone started post MPTP, whereas GFAP levels remained unchanged. In conclusion, the results obtained in the present study show neuroprotective and anti-inflammatory effects of progesterone in the myenteric plexus of MPTP mice that are similar to our previous findings in the brain. Progesterone is non-feminising and could be used for both men and women in the pre-symptomatic stages of the disease.