Abstract：
OBJECTIVE: Sodium channel blockers (SCBs) have traditionally been utilized as anti-seizure medications by primarily targeting the inactivation process. In a drug discovery project aiming at finding potential anticonvulsants, we have identified arbidol, originally an antiviral drug, as a potent SCB. In order to evaluate its anticonvulsant potential, we have thoroughly examined its biophysical properties as well as its effects on animal seizure models.
METHODS: Patch clamp recording was used to investigate the electrophysiological properties of arbidol, as well as the binding and unbinding kinetics of arbidol, carbamazepine and lacosamide. Furthermore, we evaluated the anticonvulsant effects of arbidol using three different seizure models in male mice.
RESULTS: Arbidol effectively suppressed neuronal epileptiform activity by blocking sodium channels. Arbidol demonstrated a distinct mode of action by interacting with both the fast and slow inactivation of Nav1.2 channels compared with carbamazepine and lacosamide. A kinetic study suggested that the binding and unbinding rates might be associated with the specific characteristics of these three drugs. Arbidol targeted the classical binding site of local anaesthetics, effectively inhibited the gain-of-function effects of Nav1.2 epileptic mutations and exhibited varying degrees of anticonvulsant effects in the maximal electroshock model and subcutaneous pentylenetetrazol model but had no effect in the pilocarpine-induced status epilepticus model.
CONCLUSIONS: Arbidol shows promising potential as an anticonvulsant agent, providing a unique mode of action that sets it apart from existing SCBs.
METHODS: Patch clamp recording was used to investigate the electrophysiological properties of arbidol, as well as the binding and unbinding kinetics of arbidol, carbamazepine and lacosamide. Furthermore, we evaluated the anticonvulsant effects of arbidol using three different seizure models in male mice.
RESULTS: Arbidol effectively suppressed neuronal epileptiform activity by blocking sodium channels. Arbidol demonstrated a distinct mode of action by interacting with both the fast and slow inactivation of Nav1.2 channels compared with carbamazepine and lacosamide. A kinetic study suggested that the binding and unbinding rates might be associated with the specific characteristics of these three drugs. Arbidol targeted the classical binding site of local anaesthetics, effectively inhibited the gain-of-function effects of Nav1.2 epileptic mutations and exhibited varying degrees of anticonvulsant effects in the maximal electroshock model and subcutaneous pentylenetetrazol model but had no effect in the pilocarpine-induced status epilepticus model.
CONCLUSIONS: Arbidol shows promising potential as an anticonvulsant agent, providing a unique mode of action that sets it apart from existing SCBs.
摘要：
目的：钠通道阻滞剂（SCB）传统上被用作主要针对灭活过程的抗癫痫药物。在一个旨在寻找潜在抗惊厥药的药物发现项目中，我们已经确认了阿比多,最初是一种抗病毒药物，作为一个有效的SCB。为了评估其抗惊厥潜力，我们已经彻底检查了它的生物物理特性以及它对动物癫痫模型的影响。
方法：使用膜片钳记录来研究阿比多尔的电生理特性，以及阿比多尔的结合和解结合动力学，卡马西平和拉科沙胺.此外，我们使用三种不同的癫痫发作模型在雄性小鼠中评估了阿比妥的抗惊厥作用。
结果：Arbidol通过阻断钠通道有效抑制神经元癫痫样活动。与卡马西平和拉科沙胺相比，Arbidol通过与Nav1.2通道的快速和缓慢失活相互作用而表现出独特的作用方式。动力学研究表明，结合和非结合速率可能与这三种药物的特定特征有关。Arbidol靶向局部麻醉剂的经典结合位点，有效抑制Nav1.2癫痫突变的功能获得效应,在最大电休克模型和皮下戊四氮模型中表现出不同程度的抗惊厥作用,但在毛果芸香碱诱导的癫痫持续状态模型中没有作用.
结论：阿比多显示出作为抗惊厥药的潜力，提供一种独特的行动模式，使其与现有的SCB区分开来。
方法：使用膜片钳记录来研究阿比多尔的电生理特性，以及阿比多尔的结合和解结合动力学，卡马西平和拉科沙胺.此外，我们使用三种不同的癫痫发作模型在雄性小鼠中评估了阿比妥的抗惊厥作用。
结果：Arbidol通过阻断钠通道有效抑制神经元癫痫样活动。与卡马西平和拉科沙胺相比，Arbidol通过与Nav1.2通道的快速和缓慢失活相互作用而表现出独特的作用方式。动力学研究表明，结合和非结合速率可能与这三种药物的特定特征有关。Arbidol靶向局部麻醉剂的经典结合位点，有效抑制Nav1.2癫痫突变的功能获得效应,在最大电休克模型和皮下戊四氮模型中表现出不同程度的抗惊厥作用,但在毛果芸香碱诱导的癫痫持续状态模型中没有作用.
结论：阿比多显示出作为抗惊厥药的潜力，提供一种独特的行动模式，使其与现有的SCB区分开来。
