title: Inhibition of prostaglandin E2 EP3 receptors improves stroke injury via anti-inflammatory and anti-apoptotic mechanisms.
abstract: Although deletion of EP3 receptors is known to ameliorate stroke injury in experimental stroke models, the underlying mechanisms and the effects of EP3-specific antagonists remain poorly understood. Here we demonstrate the protective effect of postischemic treatment with an EP3 antagonist, ONO-AE3-240, through anti-inflammatory and anti-apoptotic effects. In transient focal ischemia models, peritoneal injection of an EP3 antagonist after occlusion-reperfusion reduced infarction, edema and neurological dysfunctions to almost the same levels of those in EP3 knockout (KO) mice. Furthermore, neuronal apoptosis in the ischemic cortex investigated by terminal dUTP nick-end labeling (TUNEL) and caspase-3 immunostaining were ameliorated in EP3 antagonist-treated mice or EP3 KO mice as compared with vehicle-treated mice or wild-type (WT) mice, respectively. There were no significant differences between ONO-AE3-240-injected or EP3 KO mice and vehicle-injected or WT mice, respectively, in mean arterial blood pressure, cerebral blood flow or body temperature. The double-immunostaining showed that EP3 receptor-positive cells were also positive for CD-11b and partially for Neu-N, the marker for microglia and neurons. Deletion of EP3 receptors also reduced damage of the blood-brain barrier, activation of microglia and infiltration of neutrophils into the ischemic cortex. These results suggest that EP3 receptors are involved in stroke injury through the enhancement of inflammatory and apoptotic reactions in the ischemic cortex. Thus, EP3 antagonists may be valuable for the 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: Yuri
authors.initials: Y
authors.lastname: Ikeda-Matsuo
authors.forename: Hayato
authors.initials: H
authors.lastname: Tanji
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001831:Body Temperature; D020520:Brain Infarction / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D062793:Occludin; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors
chemical_list: C100745:Aif1 protein, rat; D000813:Anilides; D000893:Anti-Inflammatory Agents; D001565:Benzoates; D002135:Calcium-Binding Proteins; D007074:Immunoglobulin G; D008565:Membrane Proteins; D008840:Microfilament Proteins; C568985:OCLN protein, human; C567964:ONO-AE3-240; D062793:Occludin; C568986:Ocln protein, mouse; C568987:Ocln protein, rat; C545648:Ptger3 protein, mouse; D058308:Receptors, Prostaglandin E, EP3 Subtype