title: Prostaglandin EP4 receptor agonist protects against acute neurotoxicity.
abstract: Under various abnormal physiologic conditions, overactivation of glutamate-gated ion channel receptor family members, including NMDA receptors, causes increase in COX-2 expression and generation of prostaglandins. PGE(2) exerts its physiologic actions mainly through its PGE(2) prostanoid (EP) receptors. In the present study, the role of the EP4 receptor against NMDA-induced excitotoxicity was investigated. Using the EP4 receptor agonist ONO-AE1-329, which has relative selectivity toward murine EP receptors on the order of EP1:EP2:EP3:EP4 of >1000:210:120:1, respectively, we questioned whether activation of the EP4 receptors has the potential to attenuate injury in brain. Mice were pretreated by intracerebroventricular injection with different doses of ONO-AE1-329 (0.1, 1, and 10 nmol; n = 9/group) and, after 20 min, by a single unilateral intrastriatal injection of NMDA (15 nmol, n = 12). NMDA injection produced a significant lesion in the ipsilateral striatum. This lesion volume was significantly reduced in groups that were pretreated with ONO-AE1-329, with maximum protection of more than 32% at 10 nmol. This is the first study revealing the protective effect of ONO-AE1-329 in an acute model of excitotoxicity in brain, and it suggests that preferential stimulation of EP4 receptors attenuates excitotoxic brain injury.
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Abdullah Shafique
authors.initials: AS
authors.lastname: Ahmad
authors.forename: Muzamil
authors.initials: M
authors.lastname: Ahmad
authors.forename: Artur Jose
authors.initials: AJ
authors.lastname: de Brum-Fernandes
authors.forename: Sylvain
authors.initials: S
authors.lastname: Doré
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D008738:Methyl Ethers / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000517:prevention & control*; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058309:Receptors, Prostaglandin E, EP4 Subtype
chemical_list: D008738:Methyl Ethers; D018696:Neuroprotective Agents; C461399:ONO-AE1-329; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype