卡维地洛可抑制癫痫相关 KCNT1 基因突变导致的神经元过度兴奋。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Chang Di, Tong Wu, Kai Gao, Na Li, Huifang Song, Lili Wang, Haojie Sun, Jingyun Yi, Xinran Zhang, Jiexin Chen, Mala Shah, Yuwu Jiang, Zhuo Huang
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引用次数: 0

摘要

背景和目的:KCNT1编码钠激活钾通道(Slack通道),其突变可导致多种形式的癫痫。传统抗癫痫药物对 KCNT1 突变患者的疗效有限。在此,我们描述了一名 EIMFS 患者的 KCNT1 杂合子突变 M267T。我们研究了这种突变的病理通道特性及其对神经元兴奋性的影响。此外,本研究还旨在开发一种药物,以有效预防 KCNT1 突变引起的癫痫发作:实验方法:在爪蟾卵母细胞中异源表达野生型或突变型 KCNT1 质粒,基于双电极电压钳记录进行通道特性评估和药物筛选。利用从 HEK293T 细胞中切除的内向外补片研究了单通道特性。通过子宫内电穿孔,WT 和 M267T Slack 通道被表达到雄性小鼠的海马 CA1 锥体神经元中,然后使用全细胞电流钳技术检测其电特性。利用凯尼酸诱导的雄性小鼠癫痫模型评估了卡维地洛的抗癫痫作用:主要结果:KCNT1 M267T突变通过增加单通道开放概率增强了Slack通道功能。通过筛选 16 种 FDA 批准的离子通道阻滞剂,我们发现卡维地洛可有效逆转突变诱导的功能增益通道特性。值得注意的是,小鼠海马CA1锥体神经元中的KCNT1 M267T突变影响了后超极化特性,并诱发神经元过度兴奋,而卡维地洛能抑制这一突变。此外,卡维地洛在凯宁酸诱导的癫痫模型中表现出抗癫痫作用:我们的研究结果表明,卡维地洛有望成为治疗癫痫的新候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Carvedilol inhibits neuronal hyperexcitability caused by epilepsy-associated KCNT1 mutations.

Background 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: Wild-type or mutant KCNT1 plasmids were expressed heterologously in Xenopus laevis oocytes, and channel property assessment and drug screening were performed based on two-electrode voltage-clamp recordings. The single-channel properties were investigated using the excised inside-out patches from HEK293T cells. Through in utero electroporation, WT and M267T Slack channels were expressed in the hippocampal CA1 pyramidal neurons in male mice, followed by the examination of the electrical properties using the whole-cell current-clamp technique. The kainic acid-induced epilepsy model in male mice was used to evalute the antiseizure effects of carvedilol.

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.

Conclusion and implication: Our findings suggest carvedilol as a new potential candidate for treatment of epilepsies.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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