title: Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus.
abstract: Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague-Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80-150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats.
authors: Department of Pharmacology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA. Electronic address: arojas@pharm.emory.edu.
authors: Asheebo
authors: A
authors: Rojas
authors: Department of Pharmacology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
authors: Thota
authors: T
authors: Ganesh
authors: Department of Pharmacology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
authors: Nadia
authors: N
authors: Lelutiu
authors: Department of Pharmacology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
authors: Paoula
authors: P
authors: Gueorguieva
authors: Department of Pharmacology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA.
authors: Raymond
authors: R
authors: Dingledine
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005911:Gliosis / Q000139:chemically induced; D006624:Hippocampus / Q000473:pathology; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D007531:Isoflurophate / Q000633:toxicity*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects*; D013226:Status Epilepticus / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology; D013997:Time Factors
chemical_list: D018925:Chemokines; D002800:Cholinesterase Inhibitors; D007211:Indoles; D018696:Neuroprotective Agents; D058307:Receptors, Prostaglandin E, EP2 Subtype; C000603409:TG6-10-1; D007531:Isoflurophate; D051546:Cyclooxygenase 2; D000110:Acetylcholinesterase
keywords: COX-2; DFP; EP2; Hippocampus; Inflammation; Neurodegeneration; Organophosphorus; PGE2; Status epilepticus
references: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3149-54
references: 22323596
references: Epilepsia. 2008 May;49(5):832-41
references: 18076646
references: J Biol Chem. 2013 Mar 29;288(13):9293-302
references: 23404506
references: J Neurosci. 2013 Oct 2;33(40):16016-32
references: 24089506
references: Neurobiol Dis. 2007 Jan;25(1):80-91
references: 17029965
references: Epilepsia. 2011 Dec;52(12):2315-25
references: 21955106
references: J Neurosci. 2011 Oct 19;31(42):14850-60
references: 22016518
references: Epilepsy Res. 2012 Sep;101(3):268-76
references: 22578704
references: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3591-6
references: 23401547
references: Curr Neurobiol. 2012 Jul;3(2):90-97
references: 24039349
references: Toxicol Sci. 2011 Mar;120(1):136-45
references: 21097996
references: Ann Neurol. 2005 May;57(5):758-61
references: 15852374
references: Drug Chem Toxicol. 2015 Jan;38(1):32-6
references: 24641243
references: Brain Res. 1997 Mar 14;751(1):37-46
references: 9098566
references: Psychopharmacologia. 1968 Sep 20;13(3):222-57
references: 5679627
references: J Neurosci. 2004 Jan 7;24(1):257-68
references: 14715958
references: J Neurosci Methods. 1980 Dec;3(2):129-49
references: 6110810
references: Neurobiol Dis. 2014 Mar;63:74-84
references: 24321435
references: J Neurosci. 2005 Nov 2;25(44):10180-7
references: 16267225
references: Toxicol Appl Pharmacol. 2012 Jul 15;262(2):194-204
references: 22583949
references: Neuropharmacology. 2011 Dec;61(8):1463-9
references: 21903116
references: Exp Neurol. 2003 Jul;182(1):21-34
references: 12821374
references: Ann Neurol. 2007 Jan;61(1):9-13
references: 17262854
references: Biochem Biophys Res Commun. 1999 Nov;265(1):194-9
references: 10548513
references: Toxicol Appl Pharmacol. 2011 Jun 15;253(3):261-9
references: 21513723
references: Epilepsia. 2014 Jan;55(1):17-25
references: 24446952
references: Ann Neurol. 2004 Aug;56(2):240-8
references: 15293276
references: Prostaglandins Other Lipid Mediat. 2010 Apr;91(3-4):104-12
references: 19808012
references: Neurobiol Dis. 2004 Dec;17(3):385-402
references: 15571975
references: Neurotoxicology. 2010 Dec;31(6):738-46
references: 20600289
references: Toxicol Sci. 2010 Aug;116(2):623-31
references: 20498005
references: Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
references: 4110397
references: J Neuroimmunol. 2004 Nov;156(1-2):74-87
references: 15465598
references: Ann Neurol. 2008 Sep;64(3):304-14
references: 18825663
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Epilepsy Behav. 2014 Jul;36:68-73
references: 24857811
references: Neurosci Lett. 2011 Oct 31;504(3):185-90
references: 21939736
references: Neurotoxicology. 2006 Mar;27(2):277-83
references: 16406030