The efficacy of γ-aminobutyric acid type A receptor (GABA AR) subtype-selective positive allosteric modulators in blocking tetramethylenedisulfotetramine (TETS)-induced seizure-like behavior in larval zebrafish with minimal sedation

• Published in: Toxicology and applied pharmacology 2021-09, Vol.426, p.115643-115643, Article 115643
• Main Authors: Mundy, Paige C., Pressly, Brandon, Carty, Dennis R., Yaghoobi, Bianca, Wulff, Heike, Lein, Pamela J.
• Format: Article
• Language: English
• Subjects: Benzodiazepine; Chemical Threat Agent; GABAAR; Seizures; Tetramethylenedisulfotetramine; Zebrafish
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2021.115643

The chemical threat agent tetramethylenedisulfotetramine (TETS) is a γ-aminobutyric acid type A receptor (GABA AR) antagonist that causes life threatening seizures. Currently, there is no specific antidote for TETS intoxication. TETS-induced seizures are typically treated with benzodiazepines, which function as nonselective positive allosteric modulators (PAMs) of synaptic GABAARs. The major target of TETS was recently identified as the GABAAR α2β3γ2 subtype in electrophysiological studies using recombinantly expressed receptor combinations. Here, we tested whether these in vitro findings translate in vivo by comparing the efficacy of GABAAR subunit-selective PAMs in reducing TETS-induced seizure behavior in larval zebrafish. We tested PAMs targeting α1, α2, α2/3/5, α6, ß2/3, ß1/2/3, and δ subunits and compared their efficacy to the benzodiazepine midazolam (MDZ). The data demonstrate that α2- and α6-selective PAMs (SL-651,498 and SB-205384, respectively) were effective at mitigating TETS-induced seizure-like behavior. Combinations of SB-205384 and MDZ or SL-651,498 and 2–261 (ß2/3-selective) mitigated TETS-induced seizure-like behavior at concentrations that did not elicit sedating effects in a photomotor behavioral assay, whereas MDZ alone caused sedation at the concentration required to stop seizure behavior. Isobologram analyses suggested that SB-205384 and MDZ interacted in an antagonistic fashion, while the effects of SL-651,498 and 2–261 were additive. These results further elucidate the molecular mechanism by which TETS induces seizures and provide mechanistic insight regarding specific countermeasures against this chemical convulsant. [Display omitted] •A zebrafish assay confirms the GABAAR subtype selectivity of the rodenticide TETS.•α2, α6 or ß2/3 selective PAMs mitigated TETS-induced seizure behavior in zebrafish.•The benzodiazepine midazolam (MDZ) caused sedation in photomotor assay.•Low dose MDZ combined with α6-selective PAM mitigates seizures with less sedation.•Combinations of α2 and ß2/3 selective PAMs mitigate seizures with less sedation.