摘要
探讨长期给药诱导形成的氯胺酮性膀胱炎差异代谢物变化及可能的毒性机制。本实验以雄性SpragueDawley(SD)大鼠为实验动物,随机分为对照组、氯胺酮低剂量(10 mg·kg-1)和氯胺酮高剂量(50 mg·kg-1)给药组,腹腔注射给药12周,测定大鼠2 h尿频次数,膀胱质量系数,采用酶联免疫法测定血清白介素-6(interleukin-6,IL-6)和肿瘤坏死因子(tumor necrosis factor-α,TNF-α)炎症指标。基于气相色谱-质谱联用(GC-MS)技术分析大鼠尿液代谢物图谱,运用多元统计模式识别分析。本实验获得西南医科大学动物实验中心伦理委员会批准(批准号:201901-98)。结果显示给药12周后,2 h尿频次数及膀胱质量指数低剂量组和高剂量组与对照组相比具有显著差异(P<0.05或P<0.01);血清IL-6和TNF-α炎症指标及膀胱HE染色结果显示,长期给予氯胺酮会诱导膀胱炎;根据代谢组学分析在对照组与低剂量组之间的差异代谢物为2,3-丁二醇、3-氨基异丁酸、柠檬酸、尿酸;在对照组与高剂量组之间的差异代谢物为3-氨基异丁酸、戊糖醇、柠檬酸、D-葡萄糖酸、尿酸。本研究表明,3-氨基异丁酸、柠檬酸和尿酸为共同的差异代谢物,与对照组比较,其相对浓度呈增加趋势,且在高剂量组中,其浓度增加更加显著,表明这3种差异代谢物可能与氯胺酮性膀胱炎发生发展密切相关。
The aim of the present study was to determine the metabolic changes and possible toxic mechanisms of ketamine-associated bladder toxicity.Twenty-four male Sprague-Dawley(SD)rats were randomly allocated into a control group,a low-dose group and a high-dose group.The behavior of these rats was observed every day.In addition,the weight,2 h urinary frequency and organ coefficient of the bladder were measured.Serum IL-6 and TNF-αlevels were measured using an enzyme-linked immunosorbent assay(ELISA).Urinary metabolites were analyzed using gas chromatography-mass spectrometry(GC-MS).This research was approved by the Ethics Committee of the Animal Experiment Center of Southwest Medical University(No.201901-98).After 12 weeks of administration,the frequency of 2 h urination and the bladder mass index were significantly different in the lowdose and high-dose groups compared with the control group.Serum IL-6 and TNF-αlevels were higher than those of the control group(P<0.05).Bladder HE staining showed that long-term administration of ketamine could induce cystitis.The concentrations of the three common differential metabolites,including 3-aminoisobutyric acid,citric acid and uric acid in the low-dose and the high-dose groups were increased compared with those in the control group.This study indicates that 3-aminoisobutyric acid,citric acid and uric acid and their related metabolic pathways may be closely related to ketamine-associated bladder toxicity.
作者
吴知桂
殷文贤
罗宏丽
司元楷
孙梦琦
廖林川
WU Zhi-gui;YIN Wen-xian;LUO Hong-li;SI Yuan-kai;SUN Meng-qi;LIAO Lin-chuan(Department of Pharmacy,Affiliated Hospital of Southwest Medical University,Luzhou 646000,China;Department of Pharmacy,Hospital of Traditional Chinese Medicine Affiliated to Southwest Medical University,Luzhou 646000,China;West China School of Basic Medical Sciences and Forensic Medicine,Sichuan University,Chengdu 610041,China)
出处
《药学学报》
CAS
CSCD
北大核心
2020年第8期1849-1854,共6页
Acta Pharmaceutica Sinica
基金
国家自然科学基金面上项目(81373239)
西南医科大学附属医院博士启动基金(18104)
西南医科大学校级课题(00031260)。
关键词
氯胺酮
代谢组学
膀胱炎
3-氨基异丁酸
柠檬酸
尿酸
ketamine
metabolomics
bladder toxicity
3-aminoisobutyric acid
citric acid
uric acid