PMID- 25448683 OWN - NLM STAT- MEDLINE DCOM- 20150206 LR - 20190816 IS - 1096-0333 (Electronic) IS - 0041-008X (Print) IS - 0041-008X (Linking) VI - 281 IP - 2 DP - 2014 Dec 1 TI - Post-exposure administration of diazepam combined with soluble epoxide hydrolase inhibition stops seizures and modulates neuroinflammation in a murine model of acute TETS intoxication. PG - 185-94 LID - S0041-008X(14)00362-7 [pii] LID - 10.1016/j.taap.2014.10.001 [doi] AB - Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. The convulsant action of TETS is thought to be mediated by inhibition of type A gamma-aminobutyric acid receptor (GABAAR) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a GABAAR positive allosteric modulator, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15mg/kg, ip). Administration of a high dose of diazepam (5mg/kg, ip) immediately following the second clonic seizure (approximately 20min post-TETS injection) effectively prevented progression to tonic seizures and death. However, this treatment did not prevent persistent reactive astrogliosis and microglial activation, as determined by GFAP and Iba-1 immunoreactivity and microglial cell morphology. Inhibition of soluble epoxide hydrolase (sEH) has been shown to exert potent anti-inflammatory effects and to increase survival in mice intoxicated with other GABAAR antagonists. The sEH inhibitor TUPS (1mg/kg, ip) administered immediately after the second clonic seizure did not protect TETS-intoxicated animals from tonic seizures or death. Combined administration of diazepam (5mg/kg, ip) and TUPS (1mg/kg, ip, starting 1h after diazepam and repeated every 24h) prevented TETS-induced lethality and influenced signs of neuroinflammation in some brain regions. Significantly decreased microglial activation and enhanced reactive astrogliosis were observed in the hippocampus, with no changes in the cortex. Combining an agent that targets specific anti-inflammatory mechanisms with a traditional antiseizure drug may enhance treatment outcome in TETS intoxication. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Vito, Stephen T AU - Vito ST AD - Department of Entomology, College of Agricultural and Environmental Sciences, University of California-Davis, Davis, CA 95616, United States. Electronic address: stvito@ucdavis.edu. FAU - Austin, Adam T AU - Austin AT AD - Department of Pediatrics, School of Medicine, University of California-Davis Medical Center, Sacramento, CA 95817, United States. Electronic address: aaustin@ucdavis.edu. FAU - Banks, Christopher N AU - Banks CN AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States. Electronic address: Christopher.Banks@oehha.ca.gov. FAU - Inceoglu, Bora AU - Inceoglu B AD - Department of Entomology, College of Agricultural and Environmental Sciences, University of California-Davis, Davis, CA 95616, United States. Electronic address: abinceoglu@ucdavis.edu. FAU - Bruun, Donald A AU - Bruun DA AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States. Electronic address: dabruun@ucdavis.edu. FAU - Zolkowska, Dorota AU - Zolkowska D AD - Department of Neurology, School of Medicine, University of California-Davis, Sacramento, CA 95817, United States. Electronic address: dzolkowska@gmail.com. FAU - Tancredi, Daniel J AU - Tancredi DJ AD - Department of Pediatrics, School of Medicine, University of California-Davis Medical Center, Sacramento, CA 95817, United States. Electronic address: djtancredi@ucdavis.edu. FAU - Rogawski, Michael A AU - Rogawski MA AD - Department of Neurology, School of Medicine, University of California-Davis, Sacramento, CA 95817, United States. Electronic address: rogawski@ucdavis.edu. FAU - Hammock, Bruce D AU - Hammock BD AD - Department of Entomology, College of Agricultural and Environmental Sciences, University of California-Davis, Davis, CA 95616, United States. Electronic address: bdhammock@ucdavis.edu. FAU - Lein, Pamela J AU - Lein PJ AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States. Electronic address: pjlein@ucdavis.edu. LA - eng GR - T32 ES007059/ES/NIEHS NIH HHS/United States GR - T32 GM099608/GM/NIGMS NIH HHS/United States GR - U54 HD079125/HD/NICHD NIH HHS/United States GR - U54 NS079202/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141014 PL - United States TA - Toxicol Appl Pharmacol JT - Toxicology and applied pharmacology JID - 0416575 RN - 0 (1-(1-methanesulfonylpiperidin-4-yl)-3-(4-trifluoromethoxyphenyl)urea) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Anticonvulsants) RN - 0 (Bridged-Ring Compounds) RN - 0 (Enzyme Inhibitors) RN - 0 (GABA Modulators) RN - 0 (Phenylurea Compounds) RN - 0 (Piperidines) RN - EC 3.3.2.- (Epoxide Hydrolases) RN - EC 3.3.2.10 (Ephx2 protein, mouse) RN - F6TS3WME05 (tetramethylenedisulfotetramine) RN - Q3JTX2Q7TU (Diazepam) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*administration & dosage MH - Anticonvulsants/*administration & dosage MH - Brain/*drug effects/enzymology/physiopathology MH - Brain Waves/drug effects MH - *Bridged-Ring Compounds MH - Diazepam/*administration & dosage MH - Disease Models, Animal MH - Drug Administration Schedule MH - Drug Therapy, Combination MH - Electroencephalography MH - Encephalitis/chemically induced/enzymology/physiopathology/*prevention & control MH - Enzyme Inhibitors/*administration & dosage MH - Epoxide Hydrolases/*antagonists & inhibitors/metabolism MH - GABA Modulators/*administration & dosage MH - Male MH - Mice MH - Phenylurea Compounds/*administration & dosage MH - Piperidines/*administration & dosage MH - Seizures/chemically induced/enzymology/physiopathology/*prevention & control MH - Time Factors PMC - PMC4258121 MID - NIHMS635183 OTO - NOTNLM OT - Benzodiazepine OT - Diazepam OT - Neuroinflammation OT - Seizure OT - Soluble epoxide hydrolase OT - Tetramethylenedisulfotetramine EDAT- 2014/12/03 06:00 MHDA- 2015/02/07 06:00 PMCR- 2015/12/01 CRDT- 2014/12/03 06:00 PHST- 2014/07/17 00:00 [received] PHST- 2014/09/19 00:00 [revised] PHST- 2014/10/02 00:00 [accepted] PHST- 2014/12/03 06:00 [entrez] PHST- 2014/12/03 06:00 [pubmed] PHST- 2015/02/07 06:00 [medline] PHST- 2015/12/01 00:00 [pmc-release] AID - S0041-008X(14)00362-7 [pii] AID - 10.1016/j.taap.2014.10.001 [doi] PST - ppublish SO - Toxicol Appl Pharmacol. 2014 Dec 1;281(2):185-94. doi: 10.1016/j.taap.2014.10.001. Epub 2014 Oct 14.