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J Neuroimmune Pharmacol. 2017 Jun;12(2):292-304. doi: 10.1007/s11481-016-9713-6. Epub 2016 Oct 12.

Anti-Inflammatory and Neuroprotective Effects of PGE2 EP4 Signaling in Models of Parkinson's Disease.

Author information

1
Neurosciences Graduate Program, Stanford University, Stanford, CA, USA. suraj16pradhan@gmail.com.
2
C1 Consulting, San Francisco, CA, USA. suraj16pradhan@gmail.com.
3
Neurobiology Graduate Program, University of California Irvine, Irvine, CA, USA.
4
Profusa, South San Francisco, CA, USA.
5
SRI International, Menlo Park, CA, USA.
6
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
7
Atreca, Redwood City, CA, USA.

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 PGE2 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;EP4lox/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.

KEYWORDS:

Alpha synuclein; EP4 receptor; GPCR; Microglia; Neuroinflammation; PGE2; Parkinson’s disease

PMID:
27734267
PMCID:
PMC5389937
DOI:
10.1007/s11481-016-9713-6
[Indexed for MEDLINE]
Free PMC Article

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