Anti-Inflammatory and Neuroprotective Effects of PGE 2 EP4 Signaling in Models of Parkinson's Disease

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

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Cells, Cultured
  • Dinoprostone / metabolism*
  • Male
  • Methyl Ethers / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / prevention & control
  • Receptors, Prostaglandin E, EP4 Subtype / agonists
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*

Substances

  • Anti-Inflammatory Agents
  • Methyl Ethers
  • Neuroprotective Agents
  • ONO-AE1-329
  • Ptger4 protein, mouse
  • Receptors, Prostaglandin E, EP4 Subtype
  • Dinoprostone