Identification of Guaifenesin–Andrographolide as a Novel Combinatorial Drug Therapy for Epilepsy Using Network Virtual Screening and Experimental Validation
Identification of Guaifenesin–Andrographolide as a Novel Combinatorial Drug Therapy for Epilepsy Using Network Virtual Screening and Experimental Validation
复制标题
使用网络虚拟筛选和实验验证鉴定愈创木酚甘油醚 - 穿心莲内酯作为癫痫的新型组合药物疗法
DOI：
10.1021/acschemneuro.1c00774
复制
发表时间：
2022
影响因子：
5
通讯作者：
Jian Li
中科院分区：
文献类型：
--
作者：
Yunyuan Huang;Haiyan Xu;Pei Wang;Rurong Gu;Xiaokang Li;Yixiang Xu;Jiqun Wang;Sicong Qiao;Donglei Shi;Zhaobing Gao;Jian Li
组合药物治疗作为一种新兴的治疗具有复杂病理机制的疾病的策略已经引起了人们的极大关注。我们以前开发了一种潜在的通用计算筛选方法，用于组合药物，并使用这种方法成功地确定了一些治疗心力衰竭的有益组合。在此，该筛选方法用于在批准的药物库中鉴定用于治疗癫痫的新型组合药物。愈创甘油醚-穿心莲内酯的组合首次被发现是在体内最大电休克（MES）和皮下戊四唑（sc-PTZ）诱导的癫痫模型中具有协同抗惊厥活性的有前景的疗法。网络分析、荧光成像和N-甲基-d-天冬氨酸（NMDA）诱导的细胞毒性研究进一步揭示愈创木酚甘油醚-穿心莲内酯可能协同影响NMDA受体，从而减轻癫痫的发病。因此，我们报告说，愈创甘油醚-穿心莲内酯的组合通过一种新的协同机制发挥抗癫痫作用，因此是一种潜在的治疗癫痫，为设计新的抗癫痫组合药物治疗提供了一个有前途的机制。
Combinatorial drug therapy has attracted substantial attention as an emerging strategy for the treatment of diseases with complex pathological mechanisms. We previously developed a potentially universal computational screening approach for combination drugs and used this approach to successfully identify some beneficial combinations for the treatment of heart failure. Herein, this screening approach was used to identify novel combination drugs for the treatment of epilepsy in an approved drug library. The combination of guaifenesin–andrographolide was first discovered as a promising therapy with synergistic anticonvulsant activities in maximal electroshock (MES)- and subcutaneous pentylenetetrazol (sc-PTZ)-induced epilepsy models in vivo. The studies of network analysis, fluorescence imaging, andN-methyl-d-aspartate (NMDA)-induced cytotoxicity further revealed that guaifenesin–andrographolide might synergistically affect NMDA receptors and then alleviate the pathogenesis of epilepsy. Therefore, we report that the combination of guaifenesin–andrographolide exerts effects against epilepsy through a novel synergistic mechanism and is thus a potential treatment for epilepsy, providing a promising mechanism for the design of novel combinatorial drug treatments against epilepsy.