title: Microsomal prostaglandin E synthase-1 contributes to ischaemic excitotoxicity through prostaglandin E2 EP3 receptors.
abstract: OBJECTIVE
  Although microsomal prostaglandin E synthase (mPGES)-1 is known to contribute to stroke injury, the underlying mechanisms remain poorly understood. This study examines the hypothesis that EP(3) receptors contribute to stroke injury as downstream effectors of mPGES-1 neurotoxicity through Rho kinase activation.
  
  
  METHODS
  We used a glutamate-induced excitotoxicity model in cultured rat and mouse hippocampal slices and a mouse middle cerebral artery occlusion-reperfusion model. Effects of an EP(3) receptor antagonist on neuronal damage in mPGES-1 knockout (KO) mice was compared with that in wild-type (WT) mice.
  
  
  RESULTS
  In cultures of rat hippocampal slices, the mRNAs of EP(1-4) receptors were constitutively expressed and only the EP(3) receptor antagonist ONO-AE3-240 attenuated and only the EP(3) receptor agonist ONO-AE-248 augmented glutamate-induced excitotoxicity in CA1 neurons. Hippocampal slices from mPGES-1 KO mice showed less excitotoxicity than those from WT mice and the EP(3) receptor antagonist did not attenuate the excitotoxicity. In transient focal ischaemia models, injection (i.p.) of an EP(3) antagonist reduced infarction, oedema and neurological dysfunction in WT mice, but not in mPGES-1 KO mice, which showed less injury than WT mice. EP(3) receptor agonist-induced augmentation of excitotoxicity in vitro was ameliorated by the Rho kinase inhibitor Y-27632 and Pertussis toxin. The Rho kinase inhibitor HA-1077 also ameliorated stroke injury in vivo.
  
  
  CONCLUSIONS
  Activity of mPGES-1 exacerbated stroke injury through EP(3) receptors and activation of Rho kinase and/or G(i). Thus, mPGES-1 and EP(3) receptors may be valuable therapeutic targets for treatment of human stroke.
authors.affiliation: Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan. matsuoy@pharm.kitasato-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda-Matsuo
authors.forename: H
authors.initials: H
authors.lastname: Tanji
authors.forename: A
authors.initials: A
authors.lastname: Ota
authors.forename: Y
authors.initials: Y
authors.lastname: Hirayama
authors.forename: S
authors.initials: S
authors.lastname: Uematsu
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: Y
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000188:drug therapy / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D018683:Excitatory Amino Acid Agents / Q000819:agonists / Q000037:antagonists & inhibitors / Q000633:toxicity; D005260:Female; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018683:Excitatory Amino Acid Agents; C545647:PTGER3 protein, human; C545648:Ptger3 protein, mouse; C545649:Ptger3 protein, rat; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D054460:rho-Associated Kinases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse