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

In collaboration with the Department of Pharmacology and Toxicology (Maastricht University) and the Office for Risk Assessment and Research (Netherlands Food and Consumer Product Safety Authority) we investigated the interaction of Tetrodotoxin (TTX) with pharmaceutical drugs known to also inhibit voltage-gated sodium (NaV) channels. We provide concentration-effect curves for inhibition of neuronal activity by TTX as well as by selected medicines that act on TTX-sensitive (Riluzole, Chloroquine, Fluoxetine, Valproic acid, Lamotrigine, Lidocaine) and TTX-resistant (Carbamazepine, Mexiletine, Flecainide) NaV channels. Our data show that binary mixtures of the medicines with TTX generally increased the inhibitory effect of TTX on spontaneous neuronal activity of rat cortical cells in vitro. These findings were confirmed using human iPSC-derived neuronal co-cultures, highlight the importance of including the use of pharmaceutical drugs in the risk assessment of TTX.

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