顾欣如;方思月;任维;王宏洁;杨健;司南;边宝林;赵海誉;

• 1:中国中医科学院中药研究所
• 2:北京中医药大学东直门医院
• 3:中国科学院化学研究所

摘要(Abstract)：

研究黄连解毒汤(HLJDD)中有效成分(生物碱类、环烯醚萜类和黄酮类)在阿尔茨海默病(AD)模型大鼠体内药代动力学过程,并探讨黄连解毒汤治疗阿尔茨海默病的相关性。实验分为正常组(n=6),假手术组(n=4)和模型组(n=12)。假手术组大鼠连续45 d皮下注射D-半乳糖(50 mg·kg-1)造成亚急性衰老模型,模型组大鼠在注射D-半乳糖的基础上,基底核注射Aβ25-35(4.0 g·L-1)和鹅膏蕈氨酸(2.0 g·L-1)。模型组大鼠分为黄连解毒汤单次给药组(n=6)和黄连解毒汤连续给药1周组(n=6)。采用LC-QQQ-MS方法测定不同时间点生物碱类、环烯醚萜类和黄酮类成分的血药浓度。并利用Bio-Plex多因子检测技术检测大鼠脑脊液中7个炎症因子(MIP-2,IL-1β,IL-2,IL-8,IL-10,IL-13,TNF-α)的水平。环烯醚萜类成分在AD模型大鼠体内吸收和消除较快,生物利用度高。原小檗碱型生物碱在血浆中含量较低,其AUC(药时曲线下面积)在给药1周组大鼠中高于单次给药组。黄酮类成分在大鼠体内的药时曲线出现了明显的双峰现象。黄连解毒汤给药后,AD模型大鼠脑脊液中的炎症因子表现出回调趋势,其中IL-1β/IL-10(P<0.05)出现显著性差异。基本阐述了环烯醚萜类,生物碱类和黄酮类成分(共41个化合物)在AD模型大鼠体内的药代动力学行为,黄连解毒汤能够通过调节炎症因子的水平改善阿尔茨海默病模型大鼠中枢炎症状态。

关键词(KeyWords)： 黄连解毒汤;阿尔茨海默病;药代动力学;炎症因子

Abstract:

Keywords:

基金项目(Foundation): 国家重点基础研究发展计划(973)项目(2014CB543003);; 国家自然科学基金项目(81202904);; 北京市科技新星计划项目(Z161100004916126);; 中央级公益性科研院所基本科研业务费专项(ZZ10-018-09)

作者(Author): 顾欣如;方思月;任维;王宏洁;杨健;司南;边宝林;赵海誉;

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参考文献(References)：

• [1]梅全喜.黄连解毒汤源出《肘后备急方》考辨[J].时珍国医国药,2013,24(11):2730.
• [2]Wang N,Feng Y,Tan H Y,et al.Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian Jiedu decoction in human hepatocellular carcinoma[J].J Ethnopharmacol,2015,164:309.
• [3]孙健,温庆辉,李夏,等.黄连解毒汤及其含药血清的化学成分及抗肿瘤作用对比研究[J].中国中药杂志,2006,31(18):1526.
• [4]朱华旭,张新龙,曾明飞.黄连解毒汤中小檗碱在脑缺血模型大鼠体内药动学与药效学相关性研究[J].中草药,2012,43(3):546.
• [5]Lin S C,Lin C C,Lu F J,et al.Protective and therapeutic effects of Huanglian Jiedu Tang on hepatotoxin-induced liver injuries[J].Am J Chin Med,1996,24(3/4):219.
• [6]Zhang X J,Deng Y X,Shi Q Z,et al.Hypolipidemic effect of the Chinese polyherbal Huanglian Jiedu decoction in type 2 diabetic ratsand its possible mechanism[J].Phytomedicine,2014,21(5):615.
• [7]Durairajan S S,Huang Y Y,Yuen P Y,et al.Effects of Huanglian Jiedu Tang and its modified formula on the modulation of amyloid-βprecursor protein processing in Alzheimer's disease models[J].PLo S ONE,2014,9(7):e102923.
• [8]王月古,汪弢,邱昕,等.黄连解毒汤对APP/PS1双转基因阿尔茨海默病小鼠自由基代谢及海马区病理形态学影响[J].中国中西医结合杂志,2011,31(10):1379.
• [9]刘磊,姜鹏,窦圣姗,等.黄连解毒汤的化学及药理学研究进展[J].中草药,2008,39(6):935.
• [10]郝海平,郑超湳,王广基.多组分、多靶点中药整体药代动力学研究的思考与探索[J].药学学报,2009,44(3):270.
• [11]周红潮,杜锐,王慧,等.黄芩苷药代动力学研究进展[J].中国中药杂志,2018,43(4):684.
• [12]丁光超,王芳芳,叶肖栗.黄连解毒胶囊中栀子苷在大鼠体内药代动力学研究[J].西北药学杂志,2009,24(1):50.
• [13]林雪玲,马玉芳,俞道进,等.黄连解毒散超微粉有效成分栀子苷在家兔体内的药代动力学研究[J].科技导报,2011,29(5):51.
• [14]何凤,顾晓莹,郭立玮,等.基于黄连解毒汤药动学的差异性优化中药复方制备工艺[J].中国实验方剂学杂志,2012,18(10):165.
• [15]林慧彬,张兆旺,林建群,等.黄连解毒汤中小檗碱药代动力学双室模型与药代过程模拟[C].济南:中国资源生物技术与糖工程学术研讨会,2005.
• [16]Deng Y X,We T,Xie L,et al.High-performance liquid chromatographic method for the determination and pharmacokinetic study of wogonoside in rat serum after oral administration of traditional Chinese medicinal preparation Huanglian Jiedu decoction[J].Biomed Chromatogr,2006,20(10):1098.
• [17]Sun J,Ma J S,Jin J,et al.Qualitative and quantitative determination of the main components of huanglianjiedu decoction by HPLC-UV/MS[J].Acta Pharm Sin,2006,41(4):380.
• [18]Yang Y,Wang H J,Yang J,et al.Chemical profiling and quantification of Chinese medicinal formula Huanglian Jiedu decoction,a systematic quality control strategy using ultra high performance liquid chromatography combined with hybrid quadrupole-orbitrap and triple quadrupole mass spectrometers[J].J Chromatogr A,2013,1321:88.
• [19]Lai X S,Ren J,Lu Y J,et al.Effects of acupuncture at HT7 on glucose metabolism in a rat model of Alzheimer's disease:an18F-FDGPET study[J].Acupunct Med,2016,34:215.
• [20]Hajali V,Sheibani V,Esmaeili-Mahani S,et al.Female rats are more susceptible to the deleterious effects of paradoxical sleep deprivation on cognitive performance[J].Behav Brain Res,2012,228(2):311.
• [21]Ren W,Zuo R,Wang Y N,et al.Pharmacokinetic-pharmacodynamic analysis on inflammation rat model after oral administration of Huanglian Jiedu decoction[J].PLo S ONE,2016,11(6):e0156256.
• [22]Zuo R,Wang H J,Si N,et al.LC-FT-ICR-MS analysis of the prototypes and metabolites in rat plasma after administration of Huanglian Jiedu decoction[J].Acta Pharm Sin,2014,49(2):237.
• [23]Anisman H.Considering cytokine panels[J].Brain Behav Immun,2004,18(3):221.
• [24]左冉,王宏洁,司南.LC-FT-ICR-MS方法鉴定黄连解毒汤在大鼠血浆中的原形及代谢产物研究[J].药学学报,2014,49(2):237.
• [25]Lu J,Wang J S,Kong L Y.Anti-inflammatory effects of Huanglian Jiedu decoction,its two fractions and four typical compounds[J].J Ethnopharmacol,2011,134(3):911.
• [26]Alam Q,Alam M Z,Mushtaq G.Inflammatory process in Alzheimer's and Parkinson's diseases:central role of cytokines[J].Curr Pharm Des,2016,22(5):541.
• [27]Cacabelos R,Alvarez X A,Fernández-Novoa L,et al.Brain interleukin-1 beta in Alzheimer's disease and vascular dementia[J].Methods Find Exp Clin Pharmacol,1994,16(2):141.