Neuroprotective and immunomodulatory effects of raloxifene in the myenteric plexus of a mouse model of Parkinson's disease.

TitleNeuroprotective and immunomodulatory effects of raloxifene in the myenteric plexus of a mouse model of Parkinson's disease.
Publication TypeJournal Article
Year of Publication2016
AuteursPoirier, A-A, Côté, M, Bourque, M, Morissette, M, Di Paolo, T, Soulet, D
JournalNeurobiol Aging
Volume48
Pagination61-71
Date Published2016 Dec
ISSN1558-1497
KeywordsAnimals, Anti-Inflammatory Agents, Benzodioxoles, Cells, Cultured, Cytokines, Disease Models, Animal, Dopaminergic Neurons, Inflammation Mediators, Macrophages, Myenteric Plexus, Neuroprotective Agents, NF-kappa B, Nitric Oxide, Parkinson Disease, Quinolines, Raloxifene Hydrochloride, Receptors, Estrogen, Receptors, G-Protein-Coupled, Selective Estrogen Receptor Modulators
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.

DOI10.1016/j.neurobiolaging.2016.08.004
Alternate JournalNeurobiol. Aging
PubMed ID27644075