马兜铃酸体内外抗单纯疱疹病毒作用  

Anti-herpes simplex virus effect of aristolochic acids in vitro and in vivo

作　　者：王兆琦 闫涵 孙立山 王伟[1] WANG Zhao-qi;YAN Han;SUN Li-shan;WANG Wei(School of Medicine and Pharmacy,Ocean University of China,Key Lab of Marine Drugs,Ministry of Education,Qingdao Shandong 266003,China)

机构地区：[1]中国海洋大学医药学院,海洋药物教育部重点实验室,山东青岛266003

出　　处：《中国药理学通报》2022年第12期1791-1800,共10页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 82173860,81874320);国家自然基金-山东省联合基金项目(No U1706210);山东省自然科学基金资助项目(No ZR2019ZD18,ZR2017MH013)。

摘　　要：目的研究马兜铃酸(aristolochic acids,AAs)体内外抗单纯疱疹病毒(herpes simplex virus,HSV)的作用及其机制。方法利用HSV感染非洲绿猴肾细胞(Vero)模型,通过致细胞病变效应、空斑实验、间接免疫荧光等方法探究AAs对HSV感染的体外抑制活性及其作用机制,并以HSV-1感染BALB/c小鼠模型评价AAs的体内抗HSV活性。结果AAs在Vero细胞上对HSV-1的IC_(50)值为11.12μmol·L^(-1),对HSV-2的IC_(50)值为25.42μmol·L^(-1),在25~50μmol·L^(-1)浓度范围内能明显抑制HSV感染导致的细胞病变效应,抑制病毒复制,且具有剂量依赖性。初步作用机制研究表明,AAs主要作用于病毒吸附后阶段,可明显降低病毒蛋白ICP27及gB表达,抑制HSV感染引起的膜融合但并非作用于病毒表面糖蛋白gB、gD、gH/L。AAs可减少HSV引起的炎症反应,抑制p38 MAPK和NF-κB的活化。此外,AAs可提高HSV-1感染小鼠的存活率,降低肺病毒载量,优于阿昔洛韦(acyclovir,ACV)。结论AAs具有明显的体内外抗HSV活性。Aim To investigate the inhibition effects and mechanisms of aristolochic acids(AAs)against herpes simplex virus(HSV)in vitro and in vivo.Methods The cytopathic effect(CPE),plaque assay,indirect immunofluorescence and others were used to explore the anti-HSV effects and mechanisms of aristolochic acid in Vero cells,and the in vivo anti-HSV activity of AAs was evaluated using HSV-1 infected BALB/c mouse model.Results The IC_(50) values of AAs on Vero cells were 11.12μmol·L^(-1) for HSV-1 and 25.42μmol·L^(-1) for HSV-2.AAs significantly inhibited the cytopathic effect caused by HSV infection at concentrations ranging from 25 to 50μmol·L^(-1),and reduced viral replication in a dose-dependent manner.The preliminary mechanism study showed that AAs mainly acted on the post-adsorption stage of virus life-cycle,significantly reduced the expression of viral proteins ICP27 and gB,and inhibited the membrane fusion induced by HSV but not acted on viral surface glycoproteins gB,gD,and gH/L.AAs could reduce the inflammatory response induced by HSV and inhibit the activation of p38 MAPK and NF-κB.In addition,AAs improved the survival rate of HSV-1 infected mice and reduced the viral load in both lung and spinal cord,superior to the effect of acyclovir.Conclusion AAs has significant anti-HSV activity in vitro and in vivo.

关 键 词：马兜铃酸 单纯疱疹病毒 抗病毒活性 膜融合抑制 p38 MAPK/NF-κB通路 小鼠模型 

分 类 号：R-332[医药卫生] R284.1R345.57R373R978.7