1. Academic Validation
  2. Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype

Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype

  • Sci Rep. 2017 Aug 25;7(1):9459. doi: 10.1038/s41598-017-09528-z.
Xu Kang 1 Jiange Qiu 1 2 Qianqian Li 1 Katherine A Bell 1 Yifeng Du 1 Da Woon Jung 3 Jae Yeol Lee 3 Jiukuan Hao 1 Jianxiong Jiang 4
Affiliations

Affiliations

  • 1 Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, Ohio, 45267-0514, USA.
  • 2 Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, 510632, China.
  • 3 Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • 4 Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, Ohio, 45267-0514, USA. jianxiong.jiang@uc.edu.
Abstract

Cyclooxygenase-2 (COX-2) triggers pro-inflammatory processes that can aggravate neuronal degeneration and functional impairments in many neurological conditions, mainly via producing prostaglandin E2 (PGE2) that activates four membrane receptors, EP1-EP4. However, which EP receptor is the culprit of COX-2/PGE2-mediated neuronal inflammation and degeneration remains largely unclear and presumably depends on the insult types and responding components. Herein, we demonstrated that COX-2 was induced and showed nuclear translocation in two neuronal cell lines - mouse Neuro-2a and human SH-SY5Y - after treatment with neurotoxin 6-hydroxydopamine (6-OHDA), leading to the biosynthesis of PGE2 and upregulation of pro-inflammatory cytokine interleukin-1β. Inhibiting COX-2 or microsomal prostaglandin E synthase-1 suppressed the 6-OHDA-triggered PGE2 production in these cells. Treatment with PGE2 or EP2 selective agonist butaprost, but not EP4 agonist CAY10598, increased cAMP response in both cell lines. PGE2-initiated cAMP production in these cells was blocked by our recently developed novel selective EP2 antagonists - TG4-155 and TG6-10-1, but not by EP4 selective antagonist GW627368X. The 6-OHDA-promoted cytotoxicity was largely blocked by TG4-155, TG6-10-1 or COX-2 selective inhibitor celecoxib, but not by GW627368X. Our results suggest that PGE2 receptor EP2 is a key mediator of COX-2 activity-initiated cAMP signaling in Neuro-2a and SH-SY5Y cells following 6-OHDA treatment, and contributes to oxidopamine-mediated neurotoxicity.

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