Sodium ion channels as therapeutic targets in epilepsy: a drug discovery perspective

Traditional broad-spectrum sodium channel blockers have long served as the mainstay of epilepsy therapy, yet their clinical utility is constrained by dose-limiting adverse effects and the risk of exacerbating certain genetic epilepsies. Targeting the specific Nav subtypes, including Nav1.1, Nav1.2, Nav1.3, and Nav1.6, has emerged as a promising therapeutic strategy to mitigate these liabilities. In this Perspective, we highlight the structure, physiological functions, and their pathological roles in epilepsies, and analyze the clinical status of Pan-Nav inhibitors and the recent advances in drug discovery strategies targeting Nav isoforms. We also discussed the challenges and opportunities of Nav channel inhibitors, with the aim of shedding light on future Nav drug discovery, emphasizing that the development of subtype-selective modulators represents a highly promising strategy to overcome the clinical limitations of current broad-spectrum antiepileptic therapies.