Tetramethylenedisulfotetramine: A Health Risk Compound and a Potential Chemical Warfare Agent

“…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 GABA A receptors (Bowery et al 1975 ; Large 1975 ; Dray 1975 ; Roberts et al 1981 ; Nik et al 2017 ; Pressly et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Perampanel, a potent AMPA receptor antagonist, protects against tetramethylenedisulfotetramine-induced seizures and lethality in mice: comparison with diazepam

2021

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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.

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“…Worldwide production of TETS was banned in 1984 because of its extremely low LD 50 of 100 μg/kg, which is approximately 7–10 mg in a 70 kg human, and because of its persistence in the environment ( Guan et al, 1993 , reviewed in Whitlow et al, 2005 ). Nevertheless, because of high consumer demand for effective rodenticides, TETS, which is easy and inexpensive to synthesize, remains widely available on the black market in Asian countries (reviewed in Patocka et al, 2018 ). Accidental and intentional poisonings are not uncommon in Asian countries, and typically occur through ingestion since TETS is tasteless and odorless (reviewed in Zhang et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Strain differences in the extent of brain injury in mice after tetramethylenedisulfotetramine-induced status epilepticus

et al. 2021

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Acute intoxication with tetramethylenedisulfotetramine (TETS) can trigger status epilepticus (SE) in humans. Survivors often exhibit long-term neurological effects, including electrographic abnormalities and cognitive deficits, but the pathogenic mechanisms linking the acute toxic effects of TETS to chronic outcomes are not known. Here, we use advanced in vivo imaging techniques to longitudinally monitor the neuropathological consequences of TETS-induced SE in two different mouse strains. Adult male NIH Swiss and C57BL/6J mice were injected with riluzole (10 mg/kg, i.p.), followed 10 min later by an acute dose of TETS (0.2 mg/kg in NIH Swiss; 0.3 mg/kg, i.p. in C57BL/6J) or an equal volume of vehicle (10% DMSO in 0.9% sterile saline). Different TETS doses were administered to trigger comparable seizure behavior between strains. Seizure behavior began within minutes of TETS exposure and rapidly progressed to SE that was terminated after 40 min by administration of midazolam (1.8 mg/kg, i.m.). The brains of vehicle and TETS-exposed mice were imaged using in vivo magnetic resonance (MR) and translocator protein (TSPO) positron emission tomography (PET) at 1, 3, 7, and 14 days post-exposure to monitor brain injury and neuroinflammation, respectively. When the brain scans of TETS mice were compared to those of vehicle controls, subtle and transient neuropathology was observed in both mouse strains, but more extensive and persistent TETS-induced neuropathology was observed in C57BL/6J mice. In addition, one NIH Swiss TETS mouse that did not respond to the midazolam therapy, but remained in SE for more than 2 h, displayed robust neuropathology as determined by in vivo imaging and confirmed by FluoroJade C staining and IBA-1 immunohistochemistry as readouts of neurodegeneration and neuroinflammation, respectively. These findings demonstrate that the extent of injury observed in the mouse brain after TETS-induced SE varied according to strain, dose of TETS and/or the duration of SE. These observations suggest that TETS-intoxicated humans who do not respond to antiseizure medication are at increased risk for brain injury.

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Tetramethylenedisulfotetramine: A Health Risk Compound and a Potential Chemical Warfare Agent

Cited by 12 publications

References 38 publications

Interpol review of toxicology 2016–2019

Interpol review of toxicology 2016–2019

Perampanel, a potent AMPA receptor antagonist, protects against tetramethylenedisulfotetramine-induced seizures and lethality in mice: comparison with diazepam

Strain differences in the extent of brain injury in mice after tetramethylenedisulfotetramine-induced status epilepticus

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