岩黄连总碱在抑郁模型大鼠体内的药代动力学分析  

Pharmacokinetics of Total Alkaloids of Corydalis saxicola in Depression Model Rats

作　　者：杭华茜 于美双 叶峪 黄茜 王一然 邵雪文 陈佩瑶 曹阳[1] 戴国梁[1] 居文政[1] HANG Huaxi;YU Meishuang;YE Yu;HUANG Qian;WANG Yiran;SHAO Xuewen;CHEN Peiyao;CAO Yang;DAI Guoliang;JU Wenzheng(Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210029,China)

机构地区：[1]南京中医药大学附属医院,南京210029

出　　处：《中国实验方剂学杂志》2024年第14期175-183,共9页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：江苏省基础研究计划面上项目(BK20211394);江苏省医学重点实验室项目(ZDXYS202209);江苏省重点研发计划社会发展项目(BE2023790);江苏省中医药科技发展计划面上项目(MS2021011)。

摘　　要：目的:探讨岩黄连总碱对脂多糖(LPS)诱导抑郁大鼠模型的影响,以及其中8种主要成分的药代动力学特征。方法:将雄性24只SD大鼠随机分成正常组、模型组、氟西汀组(10 mg·kg^(-1))、岩黄连总碱组(210 mg·kg^(-1)),每组6只。除正常组外,其他大鼠经腹腔注射LPS建立抑郁症炎症模型,造模1周后开始给药,各给药组按相应剂量灌胃药液,正常组及模型组灌胃等体积蒸馏水,边造模边给药。连续给药2周后,通过糖水偏好、强迫游泳及旷场试验测试岩黄连总碱对抑郁大鼠行为学的影响,酶联免疫吸附测定法(ELISA)测定大鼠血清中肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1β、IL-6水平,苏木素-伊红(HE)染色观察大鼠海马组织病理学变化。末次给药后,按设定时间经眼眶取血,采用超高效液相色谱-三重四极杆串联质谱法(UPLC-QqQ-MS)检测其中脱氢卡维丁、延胡索乙素、黄连碱、巴马汀、药根碱、小檗碱、小檗红碱、表小檗碱的血药浓度,绘制药-时曲线,通过DAS 2.0软件对各成分药代动学参数进行分析。结果:与正常组比较,模型组糖水偏好率降低、旷场总路程减少、游泳不动时间延长,血清中炎症因子表达升高(P<0.01);与模型组比较,各给药组大鼠糖水偏好率增加、旷场总路程增加,游泳不动时间缩短,岩黄连总碱组血清中炎症因子表达降低(P<0.05,P<0.01)。HE染色结果显示,模型组大鼠海马区神经元缺失、排列紊乱且有残留空泡,岩黄连总碱组大鼠海马区神经元增多且排列整齐、胞浆清楚。药代动力学结果显示,经连续灌胃岩黄连总碱后,8种活性成分的达峰时间(t_(max))为0.19~2.06 h,半衰期(t_(1/2))为3.71~8.70 h,其中延胡索乙素的药时曲线下面积(AUC_(0-∞))最高且t_(1/2)最短,黄连碱、巴马汀、药根碱、小檗碱、小檗红碱、表小檗碱的AUC_(0-∞)均较低。脱氢卡维丁、黄连碱、巴马汀、小檗碱和表小檗碱药时Objective:To investigate the effect of total alkaloids of Corydalis saxicola on a rat model of lipopolysaccharide(LPS)-induced depression,as well as the pharmacokinetic characteristics of 8 of its major components.Method:Twenty-four male SD rats were randomly divided into normal group,model group,fluoxetine group(10 mg·kg^(-1))and total alkaloids of C.saxicola group(210 mg·kg^(-1)),with 6 rats in each group.In addition to the normal group,the rats were injected intraperitoneally with LPS to establish the inflammation model of depression,and the drug administration was started 1 week after modeling,and the administration groups were gavaged according to the corresponding dose,and the normal and model groups were intragastric administration with equal volume of distilled water,and the administration was performed along with the modeling.After two weeks of continuous administration,the effect of total alkaloids of C.saxicola on the behavior of depressed rats were tested by sucrose preference,forced swimming and open field experiments,the levels of tumor necrosis factor-α(TNF-α),interleukin(IL)-1βand IL-6 in serum of rats were determined by enzyme-linked immunosorbent assay(ELISA),the histopathological changes of rat hippocampus were observed by hematoxylin-eosin(HE)staining.After the last administration,blood was collected from orbit according to the set time,and ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry(UPLC-QqQ-MS)was established to simultaneously detect the concentrations of dehydrocavidine,tetrahydropalmatine,coptisine,palmatine,jatrorrhizine,berberine,berberrubine and epiberberine in plasma,and drug-time curves were drawn.The pharmacokinetic parameters were analyzed by DAS 2.0 software.Result:Compared with the normal group,the model group exhibited a decrease in sucrose preference rate,total distance traveled in the open field,as well as an increase in swimming immobility time and serum inflammatory factor expression(P<0.01).In contrast,compared with the model

关 键 词：岩黄连总碱 抑郁模型 脂多糖(LPS) 药代动力学 超高效液相色谱-三重四级杆串联质谱法(UPLC-QqQMS) 炎症因子 

分 类 号：R22[医药卫生—中医基础理论] R943[医药卫生—中医学] R28[理学—分析化学] O657[理学—化学]