title: Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia.
abstract: The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE2, a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMP-dependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE2 receptor subtype in brain that may provide a target for therapeutic intervention.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: McCullough
authors.forename: Liejun
authors.initials: L
authors.lastname: Wu
authors.forename: Norman
authors.initials: N
authors.lastname: Haughey
authors.forename: Xibin
authors.initials: X
authors.lastname: Liang
authors.forename: Tracey
authors.initials: T
authors.lastname: Hand
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Katrin
authors.initials: K
authors.lastname: Andreasson
mesh_terms: D000818:Animals; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000473:pathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology; D002546:Ischemic Attack, Transient / Q000473:pathology*; D007527:Isoenzymes / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000032:analysis; D016548:Prosencephalon / Q000737:chemistry; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype
chemical_list: D007527:Isoenzymes; D018696:Neuroprotective Agents; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D018698:Glutamic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone