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.
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The authors would like to acknowledge Dr. Nathan Woodling and Dr. Xibin Liang for providing invaluable help in mastering the techniques and knowledge required to conduct this research. Thanks goes to Novie Ko for crucial assistance with the HPLC measurements. The authors also extend their thanks to the Stanford Human Immune Monitoring Center for providing equipment for the Luminex analysis and the Stanford Veterinary Service Center for providing the facilities necessary for housing the animals used in this research. Last but not least, the authors would like to thank Drs. Richard and Matthew Breyer (Vanderbilt University School of Medicine, Nashville, TN) for kindly providing C57BL/6 J EP4 lox/lox mice (Schneider et al., 2004) that were used in this study.
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Conflict of Interest
The authors declare that they have no conflict of interest.
SSP designed and performed all MPTP and cell culture experiments, and prepared the manuscript. KS performed ELISA analysis of conditioned media from microglia and BV2 cells. ACG assisted with sectioning of brains, and immunostaining and image analysis of brain sections. JUJ performed isolation of the peritoneal macrophages used in this study and assisted in gene expression analysis. QW assisted with logistics of various experiments, in particular the luminex analysis of conditioned media from microglia. NK performed HPLC analysis of dopamine and associated metabolites from striatal brain sections. AMB collaborated on this study by lending stereology and HPLC equipment from her lab and advised in the design of experiments. KIA provided the resources to conduct the majority of experiments, and provided guidance on experimental design and manuscript preparation. All authors have read and approved the final version of the manuscript.
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