title: Anti-Inflammatory and Neuroprotective Effects of PGE2EP4 Signaling in Models of Parkinson's Disease.
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 PGE2receptor 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;EP4lox/loxmice 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.
authors.affiliation: Neurosciences Graduate Program, Stanford University, Stanford, CA, USA. suraj16pradhan@gmail.com.|C1 Consulting, San Francisco, CA, USA. suraj16pradhan@gmail.com.
authors.forename: Suraj S
authors.initials: SS
authors.lastname: Pradhan
authors.affiliation: Neurobiology Graduate Program, University of California Irvine, Irvine, CA, USA.
authors.forename: Kirstie
authors.initials: K
authors.lastname: Salinas
authors.affiliation: Profusa, South San Francisco, CA, USA.
authors.forename: Alexis C
authors.initials: AC
authors.lastname: Garduno
authors.affiliation: SRI International, Menlo Park, CA, USA.
authors.forename: Jenny U
authors.initials: JU
authors.lastname: Johansson
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Atreca, Redwood City, CA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Manning-Bog
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Katrin I
authors.initials: KI
authors.lastname: Andreasson
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism*; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000517:prevention & control; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D008738:Methyl Ethers; D018696:Neuroprotective Agents; C461399:ONO-AE1-329; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone
keywords: Alpha synuclein; EP4 receptor; GPCR; Microglia; Neuroinflammation; PGE2; Parkinson’s disease