학술논문
Anti-Inflammatory and Neuroprotective Effects of PGE 2 EP4 Signaling in Models of Parkinson's Disease.
Document Type
Academic Journal
Author
Pradhan SS; Neurosciences Graduate Program, Stanford University, Stanford, CA, USA. suraj16pradhan@gmail.com.; C1 Consulting, San Francisco, CA, USA. suraj16pradhan@gmail.com.; Salinas K; Neurobiology Graduate Program, University of California Irvine, Irvine, CA, USA.; Garduno AC; Profusa, South San Francisco, CA, USA.; Johansson JU; SRI International, Menlo Park, CA, USA.; Wang Q; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Manning-Bog A; Atreca, Redwood City, CA, USA.; Andreasson KI; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Source
Publisher: Springer Science + Business Media Country of Publication: United States NLM ID: 101256586 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-1904 (Electronic) Linking ISSN: 15571890 NLM ISO Abbreviation: J Neuroimmune Pharmacol Subsets: MEDLINE
Subject
Language
English
Abstract
Inflammation is a ubiquitous factor accompanying normal aging and neurodegeneration, and recent studies indicate a major contribution of inducible cyclooxygenase (COX-2) and its downstream prostaglandin signaling pathways in modulating neuroinflammatory responses and neuronal function. We have previously shown that the prostaglandin PGE 2 receptor EP4 suppresses innate immune responses in models of systemic inflammation. Here we investigated the role of the EP4 receptor in models of Parkinson's disease (PD). Systemic co-administration of the EP4 agonist ONO-AE1-329 with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prevented loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) without significant changes in glial activation, suggesting a potent neuroprotective effect of EP4 signaling in this acute model of DA neuronal loss. Cell-specific conditional ablation of EP4 in Cd11bCre;EP4 lox/lox mice exacerbated MPTP-associated glial activation and T-cell infiltration in SNpc, consistent with anti-inflammatory functions of microglial EP4 signaling. In vitro, in primary microglia stimulated with oligomeric α-synuclein, EP4 receptor activation suppressed generation of pro-inflammatory and oxidative stress factors. Taken together, these findings suggest a dual neuroprotective and anti-inflammatory mechanism of action by the EP4 receptor in models of PD.