Cilantro leaf harbors a potent potassium channel-activating anticonvulsant
Cilantro leaf harbors a potent potassium channel-activating anticonvulsant
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DOI：
10.1096/fj.201900485r
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发表时间：
2019-10-01
期刊：
影响因子：
4.8
通讯作者：
Abbott, Geoffrey W.
中科院分区：
文献类型：
--
作者：
Manville, Rian W.;Abbott, Geoffrey W.
草药作为民间药物抗惊厥剂有着悠久的历史，但其潜在的机制往往仍然未知。神经元电压门控钾通道亚家族Q（KCNQ）功能障碍可导致对现代抗惊厥药耐药的严重癫痫性脑病。在这里，我们报告说，香菜（芫荽），一种广泛使用的烹饪草药，也表现出抗癫痫和其他治疗活动，是一个非常有效的KCNQ通道激活剂。香菜叶代谢物的筛选显示，长链脂肪醛（E）-2-十二烯醛激活多种KCNQ，包括主要的神经元亚型KCNQ 2/KCNQ 3 [半数最大有效浓度（EC 50），60 +/- 20 nM]，以及主要的心脏亚型KCNQ 1与I型跨膜辅助亚基（KCNE 1）复合。（EC50，260 +/- 100 nM）。（E）-2-十二烯醛也概括了香菜的抗惊厥作用，延迟戊四唑诱导的癫痫发作。计算机模拟对接和诱变研究确定了（E）-2-十二烯醛结合位点，并置在KCNQ S5跨膜片段和S4-5接头上的残基之间。这些结果为香菜的治疗作用提供了分子基础，并表明这种无处不在的烹饪草药对临床上重要的KCNQ通道具有惊人的影响力。曼维尔河W.，Abbott，G. W.芫荽叶含有一种有效的钾通道激活抗惊厥剂。
Herbs have a long history of use as folk medicine anticonvulsants, yet the underlying mechanisms often remain unknown. Neuronal voltage-gated potassium channel subfamily Q (KCNQ) dysfunction can cause severe epileptic encephalopathies that are resistant to modern anticonvulsants. Here we report that cilantro (Coriandrum sativum), a widely used culinary herb that also exhibits antiepileptic and other therapeutic activities, is a highly potent KCNQ channel activator. Screening of cilantro leaf metabolites revealed that one, the long-chain fatty aldehyde (E)-2-dodecenal, activates multiple KCNQs, including the predominant neuronal isoform, KCNQ2/KCNQ3 [half maximal effective concentration (EC50), 60 +/- 20 nM], and the predominant cardiac isoform, KCNQ1 in complexes with the type I transmembrane ancillary subunit (KCNE1) (EC50, 260 +/- 100 nM). (E)-2-dodecenal also recapitulated the anticonvulsant action of cilantro, delaying pentylene tetrazole-induced seizures. In silico docking and mutagenesis studies identified the (E)-2-dodecenal binding site, juxtaposed between residues on the KCNQ S5 transmembrane segment and S4-5 linker. The results provide a molecular basis for the therapeutic actions of cilantro and indicate that this ubiquitous culinary herb is surprisingly influential upon clinically important KCNQ channels.-Manville, R. W., Abbott, G. W. Cilantro leaf harbors a potent potassium channel-activating anticonvulsant.