The role of the prostaglandin E2 receptors in vulnerability of oligodendrocyte precursor cells to death

Abstract

BackgroundActivity of cyclooxygenase 2 (COX-2) in mouse oligodendrocyte precursor cells (OPCs) modulates vulnerability to excitotoxic challenge. The mechanism by which COX-2 renders OPCs more sensitive to excitotoxicity is not known. In the present study, we examined the hypothesis that OPC excitotoxic death is augmented by COX-2-generated prostaglandin E2 (PGE2) acting on specific prostanoid receptors which could contribute to OPC death.MethodsDispersed OPC cultures prepared from mice brains were examined for expression of PGE2 receptors and the ability to generate PGE2 following activation of glutamate receptors with kainic acid (KA). OPC death in cultures was induced by either KA, 3′-O-(Benzoyl) benzoyl ATP (BzATP) (which stimulates the purinergic receptor P2X7), or TNFα, and the effects of EP3 receptor agonists and antagonists on OPC viability were examined.ResultsStimulation of OPC cultures with KA resulted in nearly a twofold increase in PGE2. OPCs expressed all four PGE receptors (EP1–EP4) as indicated by immunofluorescence and Western blot analyses; however, EP3 was the most abundantly expressed. The EP3 receptor was identified as a candidate contributing to OPC excitotoxic death based on pharmacological evidence. Treatment of OPCs with an EP1/EP3 agonist 17 phenyl-trinor PGE2 reversed protection from a COX-2 inhibitor while inhibition of EP3 receptor protected OPCs from excitotoxicity. Inhibition with an EP1 antagonist had no effect on OPC excitotoxic death. Moreover, inhibition of EP3 was protective against toxic stimulation with KA, BzATP, or TNFα.ConclusionTherefore, inhibitors of the EP3 receptor appear to enhance survival of OPCs following toxic challenge and may help facilitate remyelination.

Reactive astrocyte COX2‐PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury

“…Our study is in general agreement with observations that blocking PGE2 production prevents systemic IL‐1β from exacerbating the extent and distribution of lesions in white matter injury (Favrais et al, ). Inhibition of PGE2 signaling also attenuates an in vitro model of excitotoxic OPC death (Carlson et al, ). Thus, in variable neurologic insults, PGE2 likely contributes to neuroglial damage through intrinsic and extrinsic pathways, and might exhibit detrimental effects on cell survival (Palumbo, Toscano, Parente, Weigert, & Bosetti, ).…”

Beneficial Effects of Spirulina Consumption on Brain Health

“…PCB administration resulted in a significant reduction in the expression levels of pro-inflammatory cytokines like IL-6 and IFN-γ in the brain, positively modulated oxidative stress markers, and preserved the integrity of myelin sheaths in the brain [ 95 ]. C-PC is a selective COX-2 inhibitor [ 22 ], and inhibition of this enzyme has been confirmed to defend oligodendrocyte precursor cells under various damage conditions [ 159 , 160 ]. Ultimately, therapies that exhibit antioxidant and anti-inflammatory effects, induce Treg and protect axons against demyelination, as demonstrated for C-PC treatment, could represent hope for MS.…”

C-Phycocyanin and Phycocyanobilin as Remyelination Therapies for Enhancing Recovery in Multiple Sclerosis and Ischemic Stroke: A Preclinical Perspective

“…OPCs cultures prepared from mice brains have also shown significant increases in PGE 2 and death levels when they are incubated with kainic acid, a compound that mediates excitotoxic insults. The kainic acid-induced deleterious effects are significantly diminished when OPCs are treated with CAY10404, a COX-2 specific inhibitor, mediated by decreasing the PGE 2 production and the subsequent inhibition of PGE 2 receptor activity [ 54 ]. Hence, this data supports the negative impact of COX-2 in OPCs survival and maturation.…”