Poirier Andrée-Anne, Côté Mélissa, Bourque Mélanie, Morissette Marc, Di Paolo Thérèse, Soulet Denis
Centre de Recherche du CHU de Québec (Pavillon CHUL), Axe Neurosciences, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
Centre de Recherche du CHU de Québec (Pavillon CHUL), Axe Neurosciences, Quebec City, Quebec, Canada; Faculty of Medicine, Department of Psychiatry and Neuroscience, Laval University, Quebec City, Quebec, Canada.
Neurobiol Aging. 2016 Dec;48:61-71. doi: 10.1016/j.neurobiolaging.2016.08.004. Epub 2016 Aug 16.
Motor symptoms in Parkinson's disease (PD) are often preceded by nonmotor symptoms related to dysfunctions of the autonomic nervous system such as constipation, defecatory problems, and delayed gastric emptying. These gastrointestinal impairments are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric plexus of the gut. Recently, we demonstrated the anti-inflammatory properties of estrogens to treat intestinal neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The present study aimed to investigate the neuroprotective and anti-inflammatory roles of raloxifene, a selective estrogen receptor modulator (SERM) already commercialized for osteoporosis treatment. In MPTP-treated mice, we found that raloxifene decreased the loss of DAergic neurons and prevented the increase in proinflammatory macrophage density in the myenteric plexus. Interestingly, raloxifene activity was prevented by the G protein-coupled estrogen receptor 1 (GPER1) antagonist G15, suggesting that raloxifene effects were mainly mediated by GPER1. Moreover, monocytic cell proinflammatory polarization, nuclear factor-kappa B (NF-κB) response, nitric oxide (NO), and proinflammatory cytokines production following 1-methyl-4-phenylpyridinium (MPP) treatment were also prevented by raloxifene in vitro. Overall, the present results suggest that raloxifene may help preventing the loss of DAergic neurons in the myenteric plexus in an MPTP mouse model of PD, at least in part through its anti-inflammatory effects. This suggests that drug repurposing of raloxifene might represent a promising therapeutic avenue to prevent systemic inflammation and peripheral neuronal dysfunction at early PD stages.
帕金森病（PD）的运动症状之前通常会出现与自主神经系统功能障碍相关的非运动症状，如便秘、排便问题和胃排空延迟。这些胃肠道损伤与肠道肌间神经丛中多巴胺能（DAergic）神经元的改变有关。最近，我们在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中证明了雌激素对治疗肠道神经变性具有抗炎特性。本研究旨在探讨雷洛昔芬的神经保护和抗炎作用，雷洛昔芬是一种已商业化用于治疗骨质疏松症的选择性雌激素受体调节剂（SERM）。在MPTP处理的小鼠中，我们发现雷洛昔芬减少了DAergic神经元的损失，并防止了肌间神经丛中促炎巨噬细胞密度的增加。有趣的是，G蛋白偶联雌激素受体1（GPER1）拮抗剂G15可阻断雷洛昔芬的活性，这表明雷洛昔芬的作用主要由GPER1介导。此外，雷洛昔芬在体外也能抑制1-甲基-4-苯基吡啶鎓（MPP）处理后单核细胞的促炎极化、核因子-κB（NF-κB）反应、一氧化氮（NO）和促炎细胞因子的产生。总体而言，目前的结果表明，雷洛昔芬可能有助于在MPTP诱导的PD小鼠模型中预防肌间神经丛中DAergic神经元的损失，至少部分是通过其抗炎作用。这表明雷洛昔芬的药物再利用可能是预防PD早期全身炎症和外周神经元功能障碍的一种有前景的治疗途径。
