Li Ni, Yan Lin, Peng Anna, Fu Xuefei, Qin Huan, Yao Kai
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, Hubei Province, China.
Neural Regen Res. 2025 Aug 13. doi: 10.4103/NRR.NRR-D-25-00260.
Voltage-gated sodium channels are essential ionic-conductance pathways in the nervous system, which play an irreplaceable role in modulating neuronal excitability and signal transduction. This review comprehensively analyzes the molecular mechanisms and pathophysiological significance of voltage-gated sodium channels, with particular emphasis on elucidating the molecular-action mechanisms of the distinct subtypes of these channels, including Nav1.1, Nav1.2, and Nav1.6, across various neurological disorders such as familial hemiplegic migraine, epilepsy, autism spectrum disorder, and retinal dysfunction. This review also provides a comprehensive overview of the pathogenic mechanisms associated with voltage-gated sodium channels, and systematically clarifies the evolutionary pathway of treatment strategies from conventional to innovative approaches. It analyzes two major categories of conventional sodium channel blockers and their applications: antiepileptic drugs (such as carbamazepine, lamotrigine, and phenytoin) and antiarrhythmic drugs (such as lidocaine, flecainide, and quinidine). However, these conventional blockers show limitations because of the lack of selectivity, driving research toward more precise therapeutic directions. Additionally, this review evaluates gabapentin, cannabidiol, and calcium channel blockers with different mechanisms of action. These drugs modulate neuronal excitability from multiple perspectives, providing diverse options for symptom relief. This review also highlights advances in gene therapy for specific diseases, such as STK-001, which promotes effective splicing of the SCN1A gene, and ETX101, which utilizes adeno-associated virus 9 vectors to deliver engineered transcription factors. These two agents provide targeted therapeutic solutions for Dravet syndrome. Furthermore, this review summarizes some innovative therapeutic agents in clinical trials, including PRAX-222 (for SCN2A gain-of-function mutation-related epilepsy), which has received Food and Drug Administration orphan drug designation, and the selective Nav1.6 inhibitor NBI-921352 (for SCN8A -related epilepsy). Collectively, this review comprehensively compares the advantages and disadvantages of conventional drugs and gene therapy and envisions future treatment strategies that integrate the strengths of both approaches, facilitating personalized precision medicine to provide more accurate and effective treatment options for patients with ion channel diseases.
电压门控钠通道是神经系统中至关重要的离子传导途径，在调节神经元兴奋性和信号转导方面发挥着不可替代的作用。本综述全面分析了电压门控钠通道的分子机制和病理生理意义，特别着重于阐明这些通道不同亚型（包括Nav1.1、Nav1.2和Nav1.6）在各种神经系统疾病（如家族性偏瘫性偏头痛、癫痫、自闭症谱系障碍和视网膜功能障碍）中的分子作用机制。本综述还全面概述了与电压门控钠通道相关的致病机制，并系统地阐明了从传统治疗方法到创新治疗方法的治疗策略演变途径。它分析了两类主要的传统钠通道阻滞剂及其应用：抗癫痫药物（如卡马西平、拉莫三嗪和苯妥英）和抗心律失常药物（如利多卡因、氟卡尼和奎尼丁）。然而，这些传统阻滞剂由于缺乏选择性而存在局限性，这推动了研究朝着更精确的治疗方向发展。此外，本综述评估了加巴喷丁、大麻二酚和具有不同作用机制的钙通道阻滞剂。这些药物从多个角度调节神经元兴奋性，为缓解症状提供了多种选择。本综述还强调了针对特定疾病的基因治疗进展，如促进SCN1A基因有效剪接的STK - 001和利用腺相关病毒9载体递送工程化转录因子的ETX101。这两种药物为德雷维特综合征提供了靶向治疗解决方案。此外，本综述总结了一些正在进行临床试验的创新治疗药物，包括已获得美国食品药品监督管理局孤儿药认定的PRAX - 222（用于SCN2A功能获得性突变相关癫痫）和选择性Nav1.6抑制剂NBI - 921352（用于SCN8A相关癫痫）。总体而言，本综述全面比较了传统药物和基因治疗的优缺点，并设想整合两种方法优势的未来治疗策略，促进个性化精准医学为离子通道疾病患者提供更准确有效的治疗选择。
