基于肾脏代谢组学探究龟龄集改善大鼠轻度认知功能障碍作用机制  

Mechanism of Guilingji to prevent the mild cognitive impairment in rats based on kidney metabonomics

作　　者：史静超 王玉昆 于舒婷 张爱荣 高晓霞[2] 秦雪梅[2] SHI Jing-chao;WANG Yu-kun;YU Shu-ting;ZHANG Ai-rong;GAO Xiao-xia;QIN Xue-mei(School of Traditional Chinese Materia Medica and Food Engineering,Shanxi University of Chinese Medicine,Jinzhong 030619,China;Modern Research Center for Traditional Chinese Medicine,Shanxi University,Taiyuan 030006,China;Taihang Herbal Research Institute,Shanxi University of Chinese Medicine,Jinzhong 030619,China;Shanxi Guangyuyuan Chinese Medicine Co.,Ltd.,Taigu 030800,China)

机构地区：[1]山西中医药大学中药与食品工程学院,山西晋中030619 [2]山西大学中医药现代研究中心,山西太原030006 [3]山西中医药大学太行本草研究院,山西晋中030619 [4]山西广誉远国药有限公司,山西太谷030800

出　　处：《药学学报》2024年第4期1017-1027,共11页Acta Pharmaceutica Sinica

基　　金：山西中医药大学科技创新能力培育计划项目(2020PY-JC-12);山西中医药大学科技创新团队(2022TD2007);山西中医药大学博士科研启动基金项目(2023BK39);名优晋药再开发山西省重点实验室(202104010910001).

摘　　要：本研究旨在从肾脏代谢组学的角度探讨龟龄集(GLJ)改善大鼠轻度认知功能障碍(MCI)的作用机制。将大鼠随机分为对照组、模型组、阳性药(银杏叶片、多奈哌齐)组和龟龄集低、高剂量组,采用颈背部皮下注射D-半乳糖同时给予半高脂饲料共8周复制MCI大鼠模型,从第5周开始给药至第8周末,测试各组大鼠肾功指标、肾脏组织病理、并基于LC-MS肾脏代谢组学的方法探究各组大鼠肾脏内源性代谢物差异,并分析代谢通路。结果显示,龟龄集可调节MCI大鼠尿素氮水平、改善肾脏组织病理损伤。阳性药银杏叶片和多奈哌齐对肾功指标无显著调节作用,银杏叶片可减轻肾脏组织病理损伤,多奈哌齐对肾组织病理无明显改善作用。肾脏代谢组学共发现23个与MCI相关的差异代谢物,龟龄集可回调其中17个代谢物。通路富集分析显示龟龄集主要通过影响肾脏半胱氨酸和甲硫氨酸代谢、烟酸与烟酰胺代谢、牛磺酸和亚牛磺酸代谢、甘油磷脂代谢发挥改善MCI的作用。研究结果初步阐明了龟龄集“从肾治脑”的药理机制,也为临床使用龟龄集治疗MCI提供了研究基础。本研究动物实验获得山西大学伦理委员会的批准(批准号:2020DW121)。This study used kidney metabolomics to investigate the underlying mechanisms of Guilingji(GLJ)on mild cognitive impairment(MCI)rats.The rats were randomly divided into 6 groups(n=8),i.e.,control group,model group,positive drug(Ginkgo biloba tablet,donepezil)group,GLJ group(low and high dose group).The MCI rat model was replicated using subcutaneous injection of D-galactose into the back of the neck along with a semi-high-fat diet for a total of 8 weeks,and drug was administered from the 5th week for 4 weeks.The kidney function and renal pathological changes of each group of rats were tested.And LC-MS based kidney metabolomics coupled with multivariate data analysis were conducted to explore the potential biomarkers,and corresponding metabolic pathways were then determined.After administration of GLJ,the level of urea nitrogen was decreased compared with those of the model group,and the abnormalities of morphology in kidney tissues were improved.The positive drugs(ginkgo biloba tablet and donepezil)had no significant modulating effect on renal function indexes.Ginkgo biloba tablet can lessen the pathological injury of kidney tissue,and donepezil had no improvement on renal histopathology.A total of 23 MCI related differential metabolites were identified in kidney,and 17 metabolites were signifcantly restored by GLJ compared with those of the model group.Additionally,we found that the cysteine and methionine metabolism,nicotinate and nicotinamide metabolism,taurine and hypotaurine metabolism,glycerophospholipid metabolism were significantly involved in the regulatory effect of GLJ.The results illuminate the"cong shen zhi nao"mechanism of GLJ,and also provide a research basis for the clinical use of GLJ for the treatment of MCI.The animal experiment of this study was approved by the Ethics Committee of Shanxi University(approval number:2020DW121).

关 键 词：轻度认知功能障碍 龟龄集 肾脏 代谢组学 通路分析 

分 类 号：R917[医药卫生—药物分析学]