基于网络药理学和实验验证探究丙戊酸致癫痫患儿肥胖的潜在作用机制  

The potential mechanism of valproic acid induced obesity in children with epilepsy based on network pharmacology and experimental verification

作　　者：周荣 王俊 梅艳[1] 李思婵 吴奔红 汪会玲 聂刚 ZHOU Rong;WANG Jun;MEI Yan;LI Sichan;WU Benhong;WANG Huiling;NIE Gang(Department of Pharmacy,Wuhan Children's Hospital,Wuhan Maternal and Child Healthcare Hospital,Tongji Medical College,Huazhong University of Science&Technology,Hubei Wuhan 430016,China;College of Chemistry,Central China Normal University,Hubei Wuhan 430079,China)

机构地区：[1]华中科技大学同济医学院附属武汉儿童医院/武汉市妇幼保健院药学部,湖北武汉430016 [2]华中师范大学化学学院,湖北武汉430079

出　　处：《中国医院药学杂志》2025年第6期644-649,共6页Chinese Journal of Hospital Pharmacy

基　　金：武汉市自然科学基金探索计划(晨光计划)-市属医疗机构临床研究重点专项(编号:2024020801020401);武汉英才-优秀青年人才计划(编号:2022068);武汉儿童医院博士启动基金项目(编号:2022FEBSJJ002);武汉儿童医院临床医学科研项目(编号:2022FE009)。

摘　　要：目的:基于网络药理学、细胞实验及临床样本检测探究丙戊酸(valproic acid,VPA)诱发癫痫患儿肥胖的潜在作用机制。方法:采用网络药理学分析VPA导致肥胖的关键靶点和通路;选取核心靶点与VPA进行分子对接。采用不同浓度的VPA刺激HepG2细胞,CCK-8检测细胞活力,荧光探针检测脂滴含量,油红O染色观察脂肪沉积。收集VPA低、中、高浓度的患者血样,用溶血磷脂酸(lysophosphatidic acid,LPA)酶联免疫吸附试剂盒检测样本中LPA的浓度。结果:网络药理学结果提示VPA导致患儿肥胖的核心靶点是LPAR6,主要作用通路是PI3K-Akt、cAMP信号通路;分子对接结果表明LPAR6与VPA能较好结合。荧光探针检测结果显示,随着VPA的浓度增加,细胞中脂滴增加。油红O染色结果显示VPA可促进细胞内的脂肪沉积,且随着浓度增加,促进作用逐渐增强。临床样本检测结果表明,随着VPA的血药浓度增加,患儿血清中LPA的浓度显著增加。结论:LPA及其受体LPAR6在VPA导致癫痫患儿肥胖中起着关键作用,其机制可能与PI3K-Akt和cAMP信号通路相关。OBJECTIVE To explore the potential mechanism of valproic acid(VPA)induced obesity in children with epilepsy based on network pharmacology,cell experiments and clinical sample detection.METHODS Network pharmacology was used to analyze the key targets and pathways of VPA-induced obesity.Molecular docking was conducted between core targets and VPA.HepG2 cells were stimulated with different concentrations of VPA.Cell viability was detected by cell counting kit-8(CCK-8)assay,lipid droplet content was detected by fluorescence probe,and fat deposition was observed by Oil Red O staining.Blood samples were collected from patients with low,medium and high concentrations of VPA and the concentration of lysophosphatidic acid(LPA)in the samples was detected by LPA enzyme-linked immunosorbent assay kit.RESULTS Network pharmacology analysis suggested that core target of VPA induced obesity in children was lysophosphatidic acid receptor 6(LPAR6),and the main involved signaling pathways were phosphoinositide 3-kinase-protein kinase B(PI3K-Akt)and cyclic adenosine monophosphate(cAMP)pathways.Molecular docking results indicated that LPAR6 could bind well with VPA.Fluorescence probe detection suggested that with the increase of VPA concentration,lipid droplets in cells increased as well.Oil Red O staining results showed that VPA could promote fat deposition in cells,with the promotional effect gradually increasing with higher concentration.The results of clinical sample detection indicated that the concentration of LPA in children's serum significantly increased with the increase of VPA blood concentration.CONCLUSION LPA and its receptor LPAR6 play a key role in obesity-induced by VPA in children with epilepsy,and the mechanism may be related to the PI3K-Akt and cAMP signaling pathways.

关 键 词：丙戊酸 癫痫 肥胖 网络药理学 LPA/LPAR6 

分 类 号：R971[医药卫生—药品]