应用蛋白质组学方法评估抗癫痫药物卡马西平对颞叶癫痫患者脑组织蛋白质组的影响

doi:10.5246/jcps.2020.01.002

中国药学(英文版) ›› 2020, Vol. 29 ›› Issue (1): 13-28.DOI: 10.5246/jcps.2020.01.002

应用蛋白质组学方法评估抗癫痫药物卡马西平对颞叶癫痫患者脑组织蛋白质组的影响

宋宇靖^1#, 赵旭阳^1#, 陈倩¹, 宋艳¹, 雷婉玉¹, 尹玉新^1*, 马维宁^2*, 黄卓^1*

1. 北京大学医学部药学院天然药物及仿生药物国家重点实验室; 分子与细胞药理学系; 基础医学院病理学系系统生物医学研究所肿瘤系统生物学重点实验室; 北京大学-清华大学生命科学联合中心, 北京 100191
2. 中国医科大学附属盛京医院神经内科, 辽宁沈阳 110000

收稿日期:2019-05-27 修回日期:2019-10-11 出版日期:2020-01-21 发布日期:2019-10-24
通讯作者: Tel.: +86-10-82805570; +86-24-96615-36316; +86-10-82805925, Fax: +86-10-82801380; +86-10-82805925; E-mail: yinyuxin@hsc.pku.edu.cn; maweining1985@163.com; huangz@hsc.pku.edu.cn
基金资助:
The Ministry of Science and Technology of China (Grant No. 2015CB559200), and the National Natural Science Foundation of China (Grant No. 81371432).

Application of proteomic approaches to assess the effect of anti-epileptic drug on seizure foci

Yujing Song^1#, Xuyang Zhao^1#, Qian Chen¹, Yan Song¹, Wanyu Lei¹, Yuxin Yin^1*, Weining Ma^2*, Zhuo Huang^1*

1. State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences; Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology; Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Neurology, Shengjing Hospital affiliated to China Medical University, Shenyang 110000, China

Received:2019-05-27 Revised:2019-10-11 Online:2020-01-21 Published:2019-10-24
Contact: Tel.: +86-10-82805570; +86-24-96615-36316; +86-10-82805925, Fax: +86-10-82801380; +86-10-82805925; E-mail: yinyuxin@hsc.pku.edu.cn; maweining1985@163.com; huangz@hsc.pku.edu.cn
Supported by:
The Ministry of Science and Technology of China (Grant No. 2015CB559200), and the National Natural Science Foundation of China (Grant No. 81371432).

摘要/Abstract

摘要：

癫痫是以痫性发作为特征的最为常见的神经系统疾病之一。抗癫痫药物(AEDs)是癫痫患者的主要治疗手段。通常人们认为抗癫痫药物通过调节离子通道的活性抑制癫痫发作。然而越来越多的证据表明,调节离子通道活性并不能完全解释抗癫痫药物对癫痫患者临床行为的众多影响。在本研究中,我们使用蛋白质组学方法来量化接受或未接受抗癫痫药物卡马西平治疗的患者海马组织中的蛋白质组。通过进一步的生物信息学分析(包括组学分析中常用的GO和KEGG分析),探究两组患者海马组织之间的蛋白质表达差异。我们发现卡马西平治疗组有400多个蛋白,包括代谢和免疫相关蛋白,表达水平高于对照组。这些被卡马西平改变的蛋白质是许多重要生物学通路中的参与者。在这些通路中,补体C3和小胶质细胞调控的免疫系统相关通路在生理条件下调节神经细胞突触的清除。在癫痫中,卡马西平诱导补体C3的上调可能导致神经元间的异常突触联系减少,从而对癫痫存在治疗作用。本研究结果提示,除调控离子通道外,卡马西平对癫痫患者的海马组织还产生多种作用,这些尚未被充分讨论的生理、药理作用可能与抗癫痫药物治疗癫痫的基本机制、产生不良反应及耐药性的机制存在重要的相关性。

关键词: 卡马西平, 蛋白质组学, 补体介导的突触消除, 谷胱甘肽S-转移酶

Abstract:

Epilepsy is one of the most common neurological disorders characterized by epileptic seizures. The anti-epileptic drugs (AEDs) are the main form of treatment for people with epilepsy. Classically, people thought that AEDs modify the activities of ion channels to suppress epileptic seizures. However, accumulating evidence suggests that targeting at ion channels cannot completely account for the numerous effects of the AEDs on its broad clinical activity in epileptic patients. In our study, proteomic methods were used to quantify the proteome of hippocampal tissues from patients who were treated or not treated by AEDs (Carbamazepine). Further bioinformatics methods, including Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, were utilized to analyze the differences between two patient groups. We found that more than 400 proteins, including metabolism and immune related proteins, had a higher expression level in the carbamazepine-treated group compared with the controls. These altered proteins were considered to be involved in many different biological pathways. Among these pathways, immune-system related pathway modulated by complement C3 and microglia was highly remarkable, which regulated the synapses elimination in physiological condition. In epilepsy, the carbamazepine induced up-regulation of complement C3 might decrease the abnormal synaptic connections between neurons and thus contribute to the therapeutic role of carbamazepine. The results of our study suggested that apart from ion channels, carbamazepine exerted numerous effects on human epileptic foci, which might be the fundamental mechanisms of AEDs for treatment, adverse-effects and pharmacoresistance of epilepsy.

Key words: Carbamazepine, Proteomics, Complement-related synaptic modification, Glutathione S-transferase enzyme

中图分类号:

R965

Supporting:

Figure S1. Schematic of possible mechanism of GST-m in AED-induced intractable epilepsy. (A)Enzymatic role of GST-m cooperating with MRP (other kinds of drug efflux transporters are also possible). (B) Schematic of non-enzymatic (regulatory) role of GST-m combined with its enzymatic role in AED-induced drug resistance of epilepsy.

Table S1. Eight proteins that participate in the biosynthesis of antibiotics were listed.

宋宇靖, 赵旭阳, 陈倩, 宋艳, 雷婉玉, 尹玉新, 马维宁, 黄卓. 应用蛋白质组学方法评估抗癫痫药物卡马西平对颞叶癫痫患者脑组织蛋白质组的影响[J]. 中国药学(英文版), 2020, 29(1): 13-28.

Yujing Song, Xuyang Zhao, Qian Chen, Yan Song, Wanyu Lei, Yuxin Yin, Weining Ma, Zhuo Huang. Application of proteomic approaches to assess the effect of anti-epileptic drug on seizure foci[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(1): 13-28.

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应用蛋白质组学方法评估抗癫痫药物卡马西平对颞叶癫痫患者脑组织蛋白质组的影响

Application of proteomic approaches to assess the effect of anti-epileptic drug on seizure foci

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