title: Neuroprotective and immunomodulatory effects of raloxifene in the myenteric plexus of a mouse model of Parkinson's disease.
abstract: 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.
authors.affiliation: Centre de Recherche du CHU de Québec (Pavillon CHUL), Axe Neurosciences, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
authors.forename: Andrée-Anne
authors.initials: AA
authors.lastname: Poirier
authors.affiliation: 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.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Côté
authors.affiliation: Centre de Recherche du CHU de Québec (Pavillon CHUL), Axe Neurosciences, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bourque
authors.affiliation: Centre de Recherche du CHU de Québec (Pavillon CHUL), Axe Neurosciences, Quebec City, Quebec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.affiliation: Centre de Recherche du CHU de Québec (Pavillon CHUL), Axe Neurosciences, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
authors.affiliation: Centre de Recherche du CHU de Québec (Pavillon CHUL), Axe Neurosciences, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada; Faculty of Medicine, Department of Psychiatry and Neuroscience, Laval University, Quebec City, Quebec, Canada. Electronic address: denis.soulet@crchul.ulaval.ca.
authors.forename: Denis
authors.initials: D
authors.lastname: Soulet
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D052117:Benzodioxoles / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D009197:Myenteric Plexus / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents; D009569:Nitric Oxide / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology*; D011804:Quinolines / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D000893:Anti-Inflammatory Agents; D052117:Benzodioxoles; D016207:Cytokines; C532507:GPER1 protein, mouse; D018836:Inflammation Mediators; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D020845:Selective Estrogen Receptor Modulators; D009569:Nitric Oxide; D020849:Raloxifene Hydrochloride
keywords: Enteric nervous system; GPER1; Gut; Hormonotherapy; Inflammation; MPTP