Abstract
Tetramethylenedisulfotetramine (TETS), a noncompetitive GABAA receptor antagonist, is a potent, highly lethal convulsant that is considered to be a chemical threat agent. Here, we assessed the ability of the AMPA receptor antagonist perampanel to protect against TETS-induced seizures and lethality in mice when administered before or after treatment with the toxicant. For comparison, we conducted parallel testing with diazepam, which is a first-line treatment for chemically induced seizures in humans. Pre-treatment of mice with either perampanel (1–4 mg/kg, i.p.) or diazepam (1–5 mg/kg, i.p.) conferred protection in a dose-dependent fashion against tonic seizures and lethality following a dose of TETS (0.2 mg/kg, i.p.) that rapidly induces seizures and death. The ED50 values for protection against mortality were 1.6 mg/kg for perampanel and 2.1 mg/kg for diazepam. Clonic seizures were unaffected by perampanel and only prevented in a minority of animals by high-dose diazepam. Neither treatment prevented myoclonic body twitches. Perampanel and diazepam also conferred protection against tonic seizures and lethality when administered 15 min following a 0.14 mg/kg, i.p., dose of TETS and 5 min following a 0.2 mg/kg, i.p., dose of TETS. Both posttreatments were highly potent at reducing tonic seizures and lethality in animals exposed to the lower dose of TETS whereas greater doses of both treatments were required in animals exposed to the larger dose of TETS. Neither treatment was as effective suppressing clonic seizures. In an experiment where 0.4 mg/kg TETS was administered by oral gavage and the treatment drugs were administered 5 min later, perampanel only partially protected against lethality whereas diazepam produced nearly complete protection. We conclude that perampanel and diazepam protect against TETS-induced tonic seizures and lethality but have less impact on clonic seizures. Both drugs could have utility in the treatment of TETS intoxication but neither eliminates all seizure activity.
Highlights
Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison (Zolkowska et al 2012; Rice et al 2017; Lauková et al 2020) considered to be a chemical threat agent by the National Institutes of Health (Jett and Spriggs 2020) and other health authorities (Patocka et al 2018)
With dosing and time course of action information in hand, we demonstrated that pretreatment with both perampanel and diazepam reduced the incidence and severity of TETS-induced tonic seizures and lethality they did not eliminate myoclonic seizures
In confirmation of a previous report by Hanada et al (2011), we found that pre-treatment with perampanel conferred protection in the maximal electroshock (MES) seizure test
Summary
Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison (Zolkowska et al 2012; Rice et al 2017; Lauková et al 2020) considered to be a chemical threat agent by the National Institutes of Health (Jett and Spriggs 2020) and other health authorities (Patocka et al 2018). TETS is believed to induce lethal seizures by blocking brain G ABAA receptors (Bowery et al 1975; Large 1975; Dray 1975; Roberts et al 1981; Nik et al 2017; Pressly et al 2021). Recent studies indicate that positive modulators of G ABAA receptors, such as diazepam, can prolong the time to onset of TETS-induced convulsions and reduce lethality (Shakarjian et al 2012; Vito et al 2014; Bruun et al 2015; Moffett et al 2019). Inhibitors of NMDA and AMPA ionotropic glutamate receptors, which are the principal mediators of fast excitatory neurotransmission in the brain, have been extensively studied as potential seizure treatments (Löscher and Rogawski 2002). While NMDA receptor antagonists are anticonvulsant in certain in vitro and in vivo models, they can paradoxically promote seizures in other situations
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