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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.
Mundy, Paige C; Pressly, Brandon; Carty, Dennis R; Yaghoobi, Bianca; Wulff, Heike; Lein, Pamela J.
Afiliación
  • Mundy PC; Department of Molecular Biosciences, University of California, School of Veterinary Medicine, Davis, CA 95616, United States. Electronic address: pacmundy@ucdavis.edu.
  • Pressly B; Department of Pharmacology, University of California, School of Medicine, Davis, CA 95616, United States. Electronic address: bpressly@ucdavis.edu.
  • Carty DR; Department of Molecular Biosciences, University of California, School of Veterinary Medicine, Davis, CA 95616, United States.
  • Yaghoobi B; Department of Molecular Biosciences, University of California, School of Veterinary Medicine, Davis, CA 95616, United States. Electronic address: byaghoobi@ucdavis.edu.
  • Wulff H; Department of Pharmacology, University of California, School of Medicine, Davis, CA 95616, United States. Electronic address: hwulff@ucdavis.edu.
  • Lein PJ; Department of Molecular Biosciences, University of California, School of Veterinary Medicine, Davis, CA 95616, United States. Electronic address: pjlein@ucdavis.edu.
Toxicol Appl Pharmacol ; 426: 115643, 2021 09 01.
Article en En | MEDLINE | ID: mdl-34265354
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 α2ß3γ2 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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Convulsiones / Hidrocarburos Aromáticos con Puentes / Receptores de GABA-A / Moduladores del GABA / Convulsivantes / Subunidades de Proteína / Hipnóticos y Sedantes Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Toxicol Appl Pharmacol Año: 2021 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Convulsiones / Hidrocarburos Aromáticos con Puentes / Receptores de GABA-A / Moduladores del GABA / Convulsivantes / Subunidades de Proteína / Hipnóticos y Sedantes Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Toxicol Appl Pharmacol Año: 2021 Tipo del documento: Article