Mixture effects of tetrodotoxin (TTX) and drugs targeting voltage-gated sodium channels on spontaneous neuronal activity in vitro

Anke M Tukker, Misha F Vrolijk, Regina G D M van Kleef, Dick T H M Sijm, Remco H S Westerink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Tetrodotoxin (TTX) potently inhibits TTX-sensitive voltage-gated sodium (Na V) channels in nerve and muscle cells, potentially resulting in depressed neurotransmission, paralysis and death from respiratory failure. Since a wide range of pharmaceutical drugs is known to also act on Na V channels, the use of medicines could predispose individuals to a higher susceptibility towards TTX toxicity. We therefore first assessed the inhibitory effect of selected medicines that act on TTX-sensitive (Riluzole, Chloroquine, Fluoxetine, Valproic acid, Lamotrigine, Lidocaine) and TTX-resistant (Carbamazepine, Mexiletine, Flecainide) Na V channels on spontaneous neuronal activity of rat primary cortical cultures grown on microelectrode arrays (MEA). After establishing concentration-effect curves, binary mixtures of the medicines with TTX at calculated NOEC, IC 20 and IC 50 values were used to determine if pharmacodynamic interactions occur between TTX and these drugs on spontaneous neuronal activity. At IC 20 and IC 50 values, all medicines significantly increased the inhibitory effect of TTX on spontaneous neuronal activity of rat cortical cells in vitro. Subsequent experiments using human iPSC-derived neuronal co-cultures grown on MEAs confirmed the ability of selected medicines (Carbamazepine, Flecainide, Riluzole, Lidocaine) to inhibit spontaneous neuronal activity. Despite the need for additional experiments using human iPSC-derived neuronal co-cultures, our combined data already highlight the importance of identifying and including vulnerable risk groups in the risk assessment of TTX.

Original languageEnglish
Pages (from-to)53-61
Number of pages9
JournalToxicology Letters
Volume373
Early online date12 Nov 2022
DOIs
Publication statusPublished - 15 Jan 2023

Keywords

  • Human induced pluripotent stem cell-derived neuronal co-cultures
  • In vitro hazard characterisation
  • Microelectrode array (MEA) recordings
  • Pharmacodynamic mixture interactions
  • Rat primary cortical cultures
  • Risk assessment

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