Back to Search
Start Over
Post-exposure administration of diazepam combined with soluble epoxide hydrolase inhibition stops seizures and modulates neuroinflammation in a murine model of acute TETS intoxication.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2014 Dec 01; Vol. 281 (2), pp. 185-94. Date of Electronic Publication: 2014 Oct 14. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Brain enzymology
Brain physiopathology
Brain Waves drug effects
Disease Models, Animal
Drug Administration Schedule
Drug Therapy, Combination
Electroencephalography
Encephalitis chemically induced
Encephalitis enzymology
Encephalitis physiopathology
Epoxide Hydrolases metabolism
Male
Mice
Seizures chemically induced
Seizures enzymology
Seizures physiopathology
Time Factors
Anti-Inflammatory Agents administration & dosage
Anticonvulsants administration & dosage
Brain drug effects
Bridged-Ring Compounds
Diazepam administration & dosage
Encephalitis prevention & control
Enzyme Inhibitors administration & dosage
Epoxide Hydrolases antagonists & inhibitors
GABA Modulators administration & dosage
Phenylurea Compounds administration & dosage
Piperidines administration & dosage
Seizures prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0333
- Volume :
- 281
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25448683
- Full Text :
- https://doi.org/10.1016/j.taap.2014.10.001