Therapeutic efficacy of voltage-gated sodium channel inhibitors in epilepsy

Abstract

Epilepsy is a neurological disease characterized by excessive and abnormal hyper-synchrony of electrical discharges of the brain and a predisposition to generate epileptic seizures resulting in a broad spectrum of neurobiological insults, imposing psychological, cognitive, social and also economic burdens to the sufferer. Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials throughout the central nervous system. Dysfunction of these channels has been implicated in the pathogenesis of epilepsy. VGSC inhibitors have been demonstrated to act as anticonvulsants to suppress the abnormal neuronal firing underlying epileptic seizures, and are used for the management and treatment of both genetic-idiopathic and acquired epilepsies. We discuss the forms of idiopathic and acquired epilepsies caused by VGSC mutations and the therapeutic efficacy of VGSC blockers in idiopathic, acquired and pharmacoresistant forms of epilepsy in this review. We conclude that there is a need for better alternative therapies that can be used alone or in combination with VGSC inhibitors in the management of epilepsies. The current anti-seizure medications (ASMs) especially for pharmacoresistant epilepsies and some other types of epilepsy have not yielded expected therapeutic efficacy partly because they do not show subtype-selectivity in blocking sodium channels while also bringing side effects. Therefore, there is a need to develop novel drug cocktails with enhanced selectivity for specific VGSC isoforms, to achieve better treatment of pharmacoresistant epilepsies and other types of epileptic seizures.