title: The dual role of prostaglandin E(2) in excitotoxicity and preconditioning-induced neuroprotection.
abstract: Cyclooxygenase-2 is harmful in models of cerebral ischemia yet plays a protective role in preconditioning-induced ischemic tolerance in the heart. This study examined the mechanisms underlying cyclooxygenase-2-mediated neurotoxicity and preconditioning-induced neuroprotection in an in vitro model of cerebral ischemia. Inhibition of cyclooxygenase-2 protects cortical neuronal cultures from death induced by oxygen-glucose deprivation and reduces oxygen-glucose deprivation-induced increases in intracellular Ca(2+) ([Ca(2+)](i)). In the present study, we determined if prostaglandin E(2) (PGE(2)) is responsible for this cyclooxygenase-2-mediated effect. Rat cortical cultures expressed mRNA for the prostanoid EP(1)-EP(4) receptors. PGE(2) reversed the attenuation in [Ca(2+)](i) and the protection offered by cyclooxygenase-2 inhibition during oxygen-glucose deprivation. These effects likely occur via activation of the prostanoid EP(1) receptor since blocking this receptor during oxygen-glucose deprivation reduced [Ca(2+)](i) and neurotoxicity. Next, we considered if the moderate activation of this pathway, by preconditioning cultures with sub-lethal oxygen-glucose deprivation, influenced the development of tolerance to an otherwise lethal oxygen-glucose deprivation insult, 48 h later. Inhibition of cyclooxygenase-2 during oxygen-glucose deprivation-preconditioning abolished preconditioning-induced protection. Furthermore, cultures were rendered tolerant to oxygen-glucose deprivation by the transient exposure to exogenous PGE(2) 24 h prior to the insult, indicating that this product of the cyclooxygenase-2 pathway is sufficient to induce ischemic tolerance. This study shows that cyclooxygenase-2 and PGE(2) are involved in both oxygen-glucose deprivation-induced neurotoxicity and preconditioning-induced neuroprotection. While neurotoxic in the context of lethal oxygen-glucose deprivation, the moderate activation of this signalling pathway confers ischemic tolerance.
authors.affiliation: University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada K1H 8M5. tania.gendron@nrc-cnrc.gc.ca
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Eric
authors.initials: E
authors.lastname: Brunette
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Tauskela
authors.forename: Paul
authors.initials: P
authors.lastname: Morley
mesh_terms: D000818:Animals; D001921:Brain; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D012531:Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D008297:Male; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011448:Prostaglandin Antagonists; C545637:Ptger1 protein, rat; C545652:Ptger4 protein, rat; D011720:Pyrazoles; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D012531:Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005947:Glucose; D015232:Dinoprostone; D002118:Calcium