胡椒提取物改善慢性束缚应激小鼠抑郁样行为的潜在机制研究  

Potential mechanism of Piper nigrum extract in improving depressive-like behaviors in chronic restraint stress mice

作　　者：贯东艳 张米佳 侯志颍 王佳音 于佳玮 范蓓[1] 谢辉[3] 段宙位[3] 白亚娟 吴宏红 王凤忠[1,2,3] 王琼 GUAN Dongyan;ZHANG Mijia;HOU Zhiying;WANG Jiayin;YU Jiawei;FAN Bei;XIE Hui;DUAN Zhouwei;BAI Yajuan;WU Honghong;WANG Fengzhong;WANG Qiong(Institute of Food Science and Technology,Chinese Academy of Agricultural Sciences,Beijing 100193,China;National Nanfan Research Institute(Sanya),Chinese Academy of Agricultural Sciences,Sanya 572024;Institute of Processing&Design of Agro-products,Hainan Academy of Agricultural Science,Haikou 571100;State Key Laboratory for Quality Research of Chinese Medicine,Macao University of Science and Technology,Macao 999078,China;Sino-Portugal TCM International Cooperation Center,the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University,Luzhou 646000)

机构地区：[1]中国农业科学院农产品加工研究所,北京100193 [2]三亚中国农业科学院国家南繁研究院,海南三亚572024 [3]海南省农业科学院农产品加工设计研究所,海口571100 [4]澳门科技大学中医药质量研究国家重点实验室,中国澳门999078 [5]西南医科大学附属中医医院中葡中医药国际合作中心,四川泸州646000

出　　处：《中国比较医学杂志》2025年第2期58-71,84,共15页Chinese Journal of Comparative Medicine

基　　金：海南省重点研发项目(ZDYF2024XDNY243);海南省财政科技计划资助(FW20230002);三亚中国农业科学院国家南繁研究院“南繁专项”项目(YYLH2307);海南省农业科学院科技创新项目(HAAS2024KJCX01)。

摘　　要：目的借助网络药理学和分子对接技术预测胡椒(Piper nigrum,PN)中的活性成分改善慢性束缚应激(chronic restraint stress,CRS)小鼠抑郁样行为的潜在机制。方法首先,利用TCMSP数据库筛选出PN主要的化学成分及靶点,通过OMIM、Genecards和FerrDB数据库获得铁死亡及抑郁症相关的靶点。取交集靶点进行GO和KEGG信号通路富集分析。其次,通过分子对接验证核心靶点与其对应的有效成分之间的结合能力。最后,建立CRS小鼠模型,用不同浓度的PN(75、150和300 mg/kg)处理4周后,进行行为学检测,并通过RT-qPCR验证核心基因表达。结果从PN中筛选出9种活性成分,对应27个靶点,抑郁症靶点8377个,铁死亡靶点547个,取三者交集得到25个靶点基因。通过KEGG富集分析发现,这些核心靶点主要富集在胆碱能突触、5-羟色胺能突触及神经活性配体-受体相互作用等信号通路中。分子对接结果表明,PN主要活性成分与CHRM2、SLC6A4、PTGS2和SLC6A2靶点具有很好的结合能力。行为学检测表明,PN能够显著提升各给药组小鼠糖水偏爱指数(P<0.01,P<0.001),降低小鼠在悬尾和强迫游泳实验中的不动时间(P<0.01,P<0.001),增加小鼠在旷场中自主探索能力(P<0.05.P<0.01,P<0.001)。ELISA结果表明,PN可以显著降低小鼠血清中炎症水平(P<0.05.P<0.01,P<0.001)。神经递质检测表明,PN可以显著提高小鼠海马中血清素和乙酰胆碱的水平(P<0.05)。RT-qPCR结果显示,PN可以下调SLC6A4 mRNA表达量(P<0.05.P<0.01,P<0.001)。结论PN可能通过调节血清素和乙酰胆碱水平,抑制炎症反应,参与免疫调节,并发挥神经保护作用,改善小鼠抑郁样行为。Objective Network pharmacology and molecular docking techniques were used to predict the potential mechanisms by which the active components of Piper nigrum(PN)regulate depressive-like behaviors in chronic restraint stress(CRS)mice.MethodsThe major chemical components and targets of PN were screened using the Traditional Chinese Medicine Systems Pharmacology database.Targets related to ferroptosis and depression were obtained from the Online Mendelian Inheritance in Man,GeneCards,and FerrDB databases.The intersecting targets were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Gnomes(KEGG)pathway enrichment analyses,and molecular docking was performed to validate the binding capacities between the core targets and their corresponding active components.Finally,we established a CRS mouse model.Mice were treated with PN 75,150,and 300 mg/kg for 4 weeks,followed by behavioral assessments and reverse transcription-quantitative polymerase chain reaction(RT-qPCR)to verify the expression of core genes.ResultsNine active components were screened from PN,corresponding to 27 targets,and 8377 targets related to depression and 547 targets associated with ferroptosis were screened from the databases.The intersection of these three sets resulted in 25 target genes.KEGG enrichment analysis revealed that these core targets were predominantly enriched in signaling pathways,including cholinergic synapses,serotonergic synapses,and neuroactive ligand-receptor interactions.Molecular docking result showed that the main active components of PN had strong binding affinities for the targets CHRM2,SLC6A4,PTGS2,and SLC6A2.Behavioral assessments demonstrated that PN significantly increased the sucrose preference index(P<0.01,P<0.001),reduced immobility time in the tail suspension and forced swimming tests(P<0.01,P<0.001),and enhanced exploratory behavior in the open field test(P<0.05.P<0.01,P<0.001).PN significantly reduced the serum levels of inflammation markers(P<0.05.P<0.01,P<0.001),as shown by enzyme-linked immunosor

关 键 词：胡椒 抑郁症 神经保护 网络药理学 

分 类 号：R-33[医药卫生]