| Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. Although large scale production of this compound has been banned internationally, it continues to be produced illegally and is considered a chemical threat agent. The best studied mechanism of the convulsant action of TETS is the inhibition of type A gamma-aminobutyric acid receptor (GABAAR) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a positive allosteric modulator of GABAAR, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15 mg/kg, ip). Administration of a high dose of diazepam (5 mg/kg, ip) immediately following the second clonic seizure (approximately 20 min post-TETS injection) effectively blocked 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 has been shown to exert potent anti-inflammatory and neuroprotective effects and to increase survival in mice intoxicated with other GABAA-R antagonists. In TETS-intoxicated mice, administration of the sEH inhibitor TUPS (1 mg/kg, ip) immediately after the second clonic seizure was not sufficient by itself to protect TETS-intoxicated mice from lethal tonic seizures. Combined administration of diazepam and TUPS (1 mg/kg, ip, starting 1 h after diazepam and repeated every 24 h) rescued mice from TETS lethality and modulated neuroinflammation in a region-dependent manner, as evidenced by significantly decreased microglial activation and enhanced reactive astrogliosis in the hippocampus, but not in the cortex. These data suggest that a combinatorial therapeutic approach targeting distinct pathogenic mechanisms of TETS intoxication may lead to more comprehensive therapeutic outcomes. |
