Tukker Anke M, Vrolijk Misha F, van Kleef Regina G D M, Sijm Dick T H M, Westerink Remco H S
Neurotoxicology Research Group, Division of Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, the Netherlands.
Faculty of Health, Medicine and Life Sciences, Department of Pharmacology and Toxicology, Maastricht University, 6229 ER Maastricht, the Netherlands.
Toxicol Lett. 2023 Jan 15;373:53-61. doi: 10.1016/j.toxlet.2022.11.005. Epub 2022 Nov 12.
Tetrodotoxin (TTX) potently inhibits TTX-sensitive voltage-gated sodium (Na) 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 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 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 and IC values were used to determine if pharmacodynamic interactions occur between TTX and these drugs on spontaneous neuronal activity. At IC and IC 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.
河豚毒素（TTX）可有效抑制神经和肌肉细胞中对TTX敏感的电压门控钠（Na）通道，可能导致神经传递抑制、麻痹以及呼吸衰竭死亡。由于已知多种药物也作用于Na通道，使用药物可能会使个体对TTX毒性更易感性增加。因此，我们首先评估了作用于对TTX敏感的（利鲁唑、氯喹、氟西汀、丙戊酸、拉莫三嗪、利多卡因）和对TTX耐药的（卡马西平、美西律、氟卡尼）Na通道的选定药物对在微电极阵列（MEA）上生长的大鼠原代皮质培养物自发神经元活动的抑制作用。在建立浓度 - 效应曲线后，将药物与TTX以计算出的无观察到效应浓度（NOEC）、半数抑制浓度（IC）和IC值进行二元混合，以确定TTX与这些药物在自发神经元活动上是否发生药效学相互作用。在IC和IC值时，所有药物均显著增强了TTX对体外大鼠皮质细胞自发神经元活动的抑制作用。随后使用在MEA上生长的人诱导多能干细胞（iPSC）衍生的神经元共培养物进行的实验证实了选定药物（卡马西平、氟卡尼、利鲁唑、利多卡因）抑制自发神经元活动的能力。尽管需要使用人iPSC衍生的神经元共培养物进行更多实验，但我们的综合数据已经凸显了在TTX风险评估中识别和纳入易感风险群体的重要性。
