Eslicarbazepine acetate (ESL) is a dibenzazepine anticonvulsant approved as adjunctive treatment for partial-onset epileptic seizures. Following first pass hydrolysis of ESL, S-licarbazepine (S-Lic) represents around 95% of circulating active metabolites. S-Lic is the main enantiomer responsible for anticonvulsant activity and this is proposed to be through the blockade of voltage-gated Na+ channels (VGSCs). ESL and S-Lic both have a voltage-dependent inhibitory effect on the Na+ current in N1E-115 neuroblastoma cells expressing neuronal VGSC subtypes including Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7. ESL has not been associated with cardiotoxicity in healthy volunteers, although a prolongation of the electrocardiographic PR interval has been observed, suggesting that ESL may also inhibit cardiac Nav1.5 isoform. However, this has not previously been studied. Here, we investigated the electrophysiological effects of ESL and S-Lic on Nav1.5 using whole-cell patch clamp recording. We interrogated two model systems: (1) MDA-MB-231 metastatic breast carcinoma cells, which endogenously express the 'neonatal' Nav1.5 splice variant, and (2) HEK-293 cells stably over-expressing the 'adult' Nav1.5 splice variant. We show that both ESL and S-Lic inhibit transient and persistent Na+ current, hyperpolarise the voltage-dependence of fast inactivation, and slow the recovery from channel inactivation. These findings highlight, for the first time, the potent inhibitory effects of ESL and S-Lic on the Nav1.5 isoform, suggesting a possible explanation for the prolonged PR interval observed in patients on ESL treatment. Given that numerous cancer cells have also been shown to express Nav1.5, and that VGSCs potentiate invasion and metastasis, this study also paves the way for future investigations into ESL and S-Lic as potential invasion inhibitors.

中文翻译：

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醋酸依卡西平和S-卡巴西平对Nav1.5通道的抑制作用

醋酸依卡西平（ESL）是一种二苯并ze庚因抗惊厥药，被批准用于部分发作性癫痫发作的辅助治疗。经过ESL的首过水解后，S-利卡西平（S-Lic）约占循环活性代谢产物的95％。S-Lic是负责抗惊厥活性的主要对映异构体，建议通过阻断电压门控的Na +通道（VGSC）来实现。ESL和S-Lic都对表达神经元VGSC亚型（包括Nav1.1，Nav1.2，Nav1.3，Nav1.6和Nav1.7）的N1E-115神经母细胞瘤细胞中的Na +电流具有电压依赖性抑制作用。尽管已观察到心电图PR间隔的延长，但ESL在健康志愿者中并未与心脏毒性相关，这表明ESL也可能抑制心脏Nav1.5亚型。然而，这以前没有被研究过。在这里，我们使用全细胞膜片钳记录研究了ESL和S-Lic对Nav1.5的电生理作用。我们询问了两个模型系统：（1）MDA-MB-231转移性乳腺癌细胞，其内源性表达“新生儿” Nav1.5剪接变体，以及（2）HEK-293细胞稳定地过表达“成人” Nav1。 5个拼接变体。我们表明，ESL和S-Lic都抑制瞬态和持续的Na +电流，使快速失活的电压依赖性超极化，并减慢通道失活的恢复速度。这些发现首次突显了ESL和S-Lic对Nav1.5亚型的有效抑制作用，这为在ESL治疗中观察到的PR间隔延长提供了可能的解释。