Prostaglandin E2 deteriorates N-methyl-D-aspartate receptor-mediated cytotoxicity possibly by activating EP2 receptors in cultured cortical neurons.
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 E2 (PGE2) have been reported to occur after cerebral ischemic insult. We therefore studied whether the COX-2 reaction product PGE2 affects glutamate receptor-mediated cell death in cultured rat cortical cells. PGE2 was found to augment NMDA-mediated cell death. The transcription of EP1, EP2, EP3 and EP4 PGE2 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-PGE2 (an EP1 agonist) and sulprostone (an EP3 agonist) had little effect. Both PGE2 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 PGE2, acting via EP2 receptors, aggravates excitotoxic neurodegeneration by a cAMP-dependent mechanism.
Takadera
Tsuneo
T
Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, 920-1148 Japan. t-takadera@hokuriku-u.ac.jp
Ohyashiki
Takao
T
D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction
D011459:Prostaglandins E, Synthetic; C545646:Ptger2 protein, rat; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone