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

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  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 0416575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0333 (Electronic) Linking ISSN: 0041008X NLM ISO Abbreviation: Toxicol Appl Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: New York, NY : Academic Press
      Original Publication: New York.
    • Subject Terms:
      Bridged-Ring Compounds* ; Convulsants*; GABA Modulators/*pharmacology ; Hypnotics and Sedatives/*pharmacology ; Protein Subunits/*physiology ; Receptors, GABA-A/*physiology ; Seizures/*chemically induced; Animals ; Behavior, Animal/drug effects ; Larva ; Locomotion/drug effects ; Midazolam/pharmacology ; Protein Subunits/genetics ; Receptors, GABA-A/genetics ; Seizures/physiopathology ; Zebrafish
    • Abstract:
      The chemical threat agent tetramethylenedisulfotetramine (TETS) is a γ-aminobutyric acid type A receptor (GABA A R) 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 GABA A Rs. The major target of TETS was recently identified as the GABA A R 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 GABA A R 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.
      (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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    • Grant Information:
      R21 NS072094 United States NS NINDS NIH HHS; R21 NS110647 United States NS NINDS NIH HHS; U54 NS079202 United States NS NINDS NIH HHS
    • Contributed Indexing:
      Keywords: Benzodiazepine; Chemical Threat Agent; GABA(A)R; Seizures; Tetramethylenedisulfotetramine; Zebrafish
    • Accession Number:
      0 (Bridged-Ring Compounds)
      0 (Convulsants)
      0 (GABA Modulators)
      0 (Hypnotics and Sedatives)
      0 (Protein Subunits)
      0 (Receptors, GABA-A)
      F6TS3WME05 (tetramethylenedisulfotetramine)
      R60L0SM5BC (Midazolam)
    • Publication Date:
      Date Created: 20210715 Date Completed: 20210806 Latest Revision: 20211015
    • Publication Date:
      20240829
    • Accession Number:
      PMC8514104
    • Accession Number:
      10.1016/j.taap.2021.115643
    • Accession Number:
      34265354