Arbidol 是一种抗病毒药物,被鉴定为具有抗惊厥活性的钠通道阻滞剂。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-07-09 DOI:10.1111/bph.16496
Min Li, Yuchen Jin, Jun Wu, Miao Zhao, Kexin Yu, Haibo Yu
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引用次数: 0

摘要

背景和目的:钠通道阻滞剂(SCB)历来被用作抗癫痫药物,主要针对失活过程。在一个旨在寻找潜在抗惊厥药物的药物发现项目中,我们发现了一种名为 arbidol 的强效钠通道阻滞剂,它最初是一种抗病毒药物。为了评估它的抗惊厥潜力,我们深入研究了它的生物物理特性及其对动物癫痫模型的影响:实验方法:我们使用膜片钳记录技术研究了阿比多尔的电生理特性,以及阿比多尔、卡马西平和拉科酰胺的结合和解除结合动力学。此外,我们还使用三种不同的癫痫模型评估了阿比多尔对雄性小鼠的抗惊厥作用:主要结果:阿比多尔通过阻断钠通道有效抑制了神经元癫痫样活动。与卡马西平和拉科酰胺相比,阿比多通过与Nav1.2通道的快速和慢速失活相互作用而显示出独特的作用模式。一项动力学研究表明,结合和解除结合的速率可能与这三种药物的特性有关。阿比多尔靶向局麻药的经典结合位点,有效抑制了Nav1.2癫痫突变的功能增益效应,并在最大电击模型和皮下注射戊四唑模型中表现出不同程度的抗惊厥作用,但在皮洛卡品诱导的癫痫状态模型中没有作用:Arbidol作为一种抗惊厥药具有广阔的潜力,其独特的作用模式使其有别于现有的SCB。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Arbidol, an antiviral drug, identified as a sodium channel blocker with anticonvulsant activity

Background and purpose

Sodium channel blockers (SCBs) have traditionally been utilized as anti-seizure medications by primarily targeting the inactivation process. In a drug discovery project aiming at finding potential anticonvulsants, we have identified arbidol, originally an antiviral drug, as a potent SCB. In order to evaluate its anticonvulsant potential, we have thoroughly examined its biophysical properties as well as its effects on animal seizure models.

Experimental approach

Patch clamp recording was used to investigate the electrophysiological properties of arbidol, as well as the binding and unbinding kinetics of arbidol, carbamazepine and lacosamide. Furthermore, we evaluated the anticonvulsant effects of arbidol using three different seizure models in male mice.

Key results

Arbidol effectively suppressed neuronal epileptiform activity by blocking sodium channels. Arbidol demonstrated a distinct mode of action by interacting with both the fast and slow inactivation of Nav1.2 channels compared with carbamazepine and lacosamide. A kinetic study suggested that the binding and unbinding rates might be associated with the specific characteristics of these three drugs. Arbidol targeted the classical binding site of local anaesthetics, effectively inhibited the gain-of-function effects of Nav1.2 epileptic mutations and exhibited varying degrees of anticonvulsant effects in the maximal electroshock model and subcutaneous pentylenetetrazol model but had no effect in the pilocarpine-induced status epilepticus model.

Conclusions and implications

Arbidol shows promising potential as an anticonvulsant agent, providing a unique mode of action that sets it apart from existing SCBs.

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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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