title: Post-exposure administration of diazepam combined with soluble epoxide hydrolase inhibition stops seizures and modulates neuroinflammation in a murine model of acute TETS intoxication.
abstract: 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.
authors.affiliation: Department of Entomology, College of Agricultural and Environmental Sciences, University of California-Davis, Davis, CA 95616, United States. Electronic address: stvito@ucdavis.edu.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Vito
authors.affiliation: Department of Pediatrics, School of Medicine, University of California-Davis Medical Center, Sacramento, CA 95817, United States. Electronic address: aaustin@ucdavis.edu.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Austin
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States. Electronic address: Christopher.Banks@oehha.ca.gov.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Banks
authors.affiliation: Department of Entomology, College of Agricultural and Environmental Sciences, University of California-Davis, Davis, CA 95616, United States. Electronic address: abinceoglu@ucdavis.edu.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States. Electronic address: dabruun@ucdavis.edu.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Bruun
authors.affiliation: Department of Neurology, School of Medicine, University of California-Davis, Sacramento, CA 95817, United States. Electronic address: dzolkowska@gmail.com.
authors.forename: Dorota
authors.initials: D
authors.lastname: Zolkowska
authors.affiliation: Department of Pediatrics, School of Medicine, University of California-Davis Medical Center, Sacramento, CA 95817, United States. Electronic address: djtancredi@ucdavis.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tancredi
authors.affiliation: Department of Neurology, School of Medicine, University of California-Davis, Sacramento, CA 95817, United States. Electronic address: rogawski@ucdavis.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rogawski
authors.affiliation: Department of Entomology, College of Agricultural and Environmental Sciences, University of California-Davis, Davis, CA 95616, United States. Electronic address: bdhammock@ucdavis.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States. Electronic address: pjlein@ucdavis.edu.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000927:Anticonvulsants / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D058256:Brain Waves / Q000187:drug effects; D001952:Bridged-Ring Compounds; D003975:Diazepam / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D004660:Encephalitis / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018757:GABA Modulators / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D012640:Seizures / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: C561619:1-(1-methanesulfonylpiperidin-4-yl)-3-(4-trifluoromethoxyphenyl)urea; D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D018757:GABA Modulators; D010671:Phenylurea Compounds; D010880:Piperidines; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; C010349:tetramethylenedisulfotetramine; D003975:Diazepam
keywords: Benzodiazepine; Diazepam; Neuroinflammation; Seizure; Soluble epoxide hydrolase; Tetramethylenedisulfotetramine