title: Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats.
abstract: Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6-12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA. Electronic address: arojas@pharm.emory.edu.
authors.forename: Asheebo
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
authors.forename: Thota
authors.initials: T
authors.lastname: Ganesh
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Manji
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
authors.forename: Theon
authors.initials: T
authors.lastname: O'neill
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Dingledine
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007531:Isoflurophate; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D018697:Nootropic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology; D013226:Status Epilepticus / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology
chemical_list: D007211:Indoles; D018697:Nootropic Agents; D058307:Receptors, Prostaglandin E, EP2 Subtype; C000603409:TG6-10-1; D007531:Isoflurophate
keywords: Anxiety; DFP; EP2 receptor; Electroencephalography; Epilepsy; Hippocampus; Light-dark box preference test; Novel object recognition; Open field; Organophosphate; Seizure; Status epilepticus