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

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.

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…As a main inflammatory mediator derived from COX-2, PGE2 can induce several proinflammatory factors, including cytokines, chemotactic factors, inducible nitric oxide synthase (iNOS) and even cOX-2 (47). These factors can promote cell proliferation, survival, angiogenesis, invasion, migration and metabolism (48). In addition, EP2 activation can significantly induce the expression of proinflammatory factors, such as interleukin (IL)-1β and IL-6 in tumor cells (42,49).…”

Neuroprotective Effects of Cornus officinalis on Stress-Induced Hippocampal Deficits in Rats and H2O2-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

“…Stress or H 2 O 2 were observed to activate MAPKs; however, CC and particularly FCC effectively inhibited MAPK family phosphorylation in both rats and cells, except that p38 MAPK in SH-SY5Y cells was not significantly reduced. Furthermore, COX-2 triggers pro-inflammatory processes that exacerbates neuronal degeneration and dysfunction in many neurological diseases [54]. We found a significant increase in COX-2 expression in the stressed rat hippocampus.…”

Untitled

“…By the use of selected NSAIDs, COX-3 is varying its sensitivity to inhibition. Diclofenac was the strongest inhibitor of cyclooxygenase-3 experienced and ibuprofen, Diclofenac, and Aspirin, preferentially inhibited cyclooxygenase-3 over cyclooxygenase-1 and -2 40,41,42,43 . Thalidomide and caffeine both have been reported as analgesic instead of COX-3 action.…”