title: Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity.
abstract: Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, has been implicated in the neurotoxicity resulting from hypoxia-ischemia, and its inhibition has therapeutic potential for ischemic stroke. However, COX-2 inhibitors increase the risk of cardiovascular complications. We therefore sought to identify the downstream effectors of COX-2 neurotoxicity, and found that prostaglandin E(2) EP1 receptors are essential for the neurotoxicity mediated by COX-2-derived prostaglandin E(2). EP1 receptors disrupt Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange, a key mechanism by which neurons cope with excess Ca(2+) accumulation after an excitotoxic insult. Thus, EP1 receptors contribute to neurotoxicity by augmenting the Ca(2+) dysregulation underlying excitotoxic neuronal death. Pharmacological inhibition or gene inactivation of EP1 receptors ameliorates brain injury induced by excitotoxicity, oxygen glucose deprivation and middle cerebral artery (MCA) occlusion. An EP1 receptor inhibitor reduces brain injury when administered 6 hours after MCA occlusion, suggesting that EP1 receptor inhibition may be a viable therapeutic option in ischemic stroke.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kawano
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Laibaik
authors.initials: L
authors.lastname: Park
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frys
authors.forename: Alexander
authors.initials: A
authors.lastname: Kunz
authors.forename: Sunghee
authors.initials: S
authors.lastname: Cho
authors.forename: Marcello
authors.initials: M
authors.lastname: Orio
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000628:therapy; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype
chemical_list: D009498:Neurotoxins; C545636:Ptger1 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D016202:N-Methylaspartate; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007608:Kainic Acid; D002118:Calcium