Prostaglandin E 2 deteriorates N-methyl- d-aspartate receptor-mediated cytotoxicity possibly by activating EP2 receptors in cultured cortical neurons

Abstract

The activation of glutamate receptors, particularly N-methyl- d-aspartate (NMDA) receptors, initiates ischemic cascade in the early stages of cerebral ischemia. Postischemia, cerebral ischemia is also associated with an inflammatory reaction that contributes to tissue damage. The up-regulation of neuronal cyclooxygenase-2 (COX-2) and elevation of prostaglandin E 2 (PGE 2) have been reported to occur after cerebral ischemic insult. We therefore studied whether the COX-2 reaction product PGE 2 affects glutamate receptor-mediated cell death in cultured rat cortical cells. PGE 2 was found to augment NMDA-mediated cell death. The transcription of EP1, EP2, EP3 and EP4 PGE 2 receptor genes was investigated using reverse transcriptase–polymerase chain reaction (RT-PCR). EP1, EP2 and EP3 receptor genes were found in cortical cells. Butaprost (an EP2 agonist) markedly enhanced NMDA-mediated cell death, whereas 17-phenyl trinor-PGE 2 (an EP1 agonist) and sulprostone (an EP3 agonist) had little effect. Both PGE 2 and butaprost elevated cAMP intracellular levels in the cortical cells; moreover, forskolin, an activator of adenylate cyclase, enhanced NMDA-mediated cell death. These results suggest that PGE 2, acting via EP2 receptors, aggravates excitotoxic neurodegeneration by a cAMP-dependent mechanism.