Di, Chang; Wu, Tong; Gao, Kai; Li, Na; Song, Huifang; Wang, Lili; Sun, Haojie; ... Huang, Zhuo; + view all Di, Chang; Wu, Tong; Gao, Kai; Li, Na; Song, Huifang; Wang, Lili; Sun, Haojie; Yi, Jingyun; Zhang, Xinran; Chen, Jiexin; Shah, Mala; Jiang, Yuwu; Huang, Zhuo; - view fewer (2024) Carvedilol inhibits neuronal hyperexcitability caused by epilepsy-associated KCNT1 mutations. British Journal of Pharmacology 10.1111/bph.17360. (In press).

Archive Shah_Carvedilol inhibits neuronal hyperexcitability caused by epilepsy-associated KCNT1 mutations_AAM.zip Access restricted to UCL open access staff until 7 October 2025. Download (24MB)

Abstract

BACKGROOUND AND PURPOSE: KCNT1 encodes a sodium-activated potassium channel (Slack channel), and its mutation can cause several forms of epilepsy. Traditional antiepileptic medications have limited efficacy in treating patients with KCNT1 mutations. Here, we describe one heterozygous KCNT1 mutation, M267T, in a patient with EIMFS. The pathological channel properties of this mutation and its effect on neuronal excitability were investigated. Additionally, this study aimed to develop a medication for effective prevention of KCNT1 mutation-induced seizures. EXPERIMENTAL APPROACH: KCNT1 encodes a sodium-activated potassium channel (Slack channel), and its mutation can cause several forms of epilepsy. Traditional antiepileptic medications have limited efficacy in treating patients with KCNT1 mutations. Here, we describe one heterozygous KCNT1 mutation, M267T, in a patient with EIMFS. The pathological channel properties of this mutation and its effect on neuronal excitability were investigated. Additionally, this study aimed to develop a medication for effective prevention of KCNT1 mutation-induced seizures. KEY RESULTS: The KCNT1 M267T mutation enhanced Slack channel function by increasing single-channel open probability. Through screening 16 FDA-approved ion channel blockers, we found that carvedilol effectively reversed the mutation-induced gain-of-function channel properties. Notably, the KCNT1 M267T mutation in the mouse hippocampal CA1 pyramidal neurons affected afterhyperpolarization properties and induced neuronal hyperexcitability, which was inhibited by carvedilol. Additionally, carvedilol exhibited antiseizure effects in the kainic acid-induced epilepsy model. CONCLUSIONS AND IMPLICATIONS: Our findings suggest carvedilol as a new potential candidate for treatment of epilepsies.

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