基于脑靶向特性研究定志小丸中石菖蒲"引药上行"作用机理

The experiments have proved the high promoting intelligence activity of saponins in Ginseng and Polygalae, but the bioavailability of these saponins is low, and they pass through the blood brain barrier difficultly. The good therapeutic effect of Dingzhi pill on Alzheimer's disease has been confirmed by clinical and animal experiments. Whether acorus gramineus (acting as adjuvant drug in compound compatibility) could improve the brain targeting and therapeutic effect of saponins? This is worthy of further study. On the basis of existing work, "intestinal absorption - brain microdialysis" dimensional model will be built in this research subject. In order to explore whether acorus gramineus could promote the intestinal absorption of constituents in prescription, the effect of acorus gramineus on intestinal absorption parameters (Ka、Papp、Q) and bioavailability of three kinds of promoting intelligence saponins (ginsenosides Rg1,Rg2、 tenuifolin) in prescription is investigated. Whether acorus gramineus could improve brain targeting of three saponins is evaluated by using brain targeting parameters（Ce、Re、DTI）study the correlation with intestinal absorption . The HPLC-MS fingerprintings of intestinal absorption and brain dialysis of whole prescription and prescription lack of acorus gramineus are established respectively and the absence of chromatographic peaks are compared to reveal the effect of acorus gramineus on intestinal absorption and changes of chemical constituents in brain. The implementation of this project could reveal the mechanism of acorus gramineus acting as "adjuvant drug" in Dingzhi pill from the perspective of drug brain targeting, and provide the basis for clinical medication scientificity of this prescription, and new ideas and methods for study of compound compatibility of traditional Chinese medicine.

人参及远志皂苷类成分具有较好益智活性，但其生物利用度低，难以透过BBB。临床和动物实验均证实定志小丸对老年痴呆症具有较好疗效,该方是否通过配伍使药石菖蒲使得益智皂苷类成分具有脑靶向性，进而发挥疗效？这是值得深入研究的问题。 本课题在已有工作基础上，拟构建"肠吸收-脑微透析"二维模型，通过考察石菖蒲对组方中三种益智皂苷类成分(人参皂苷Rg1、Rb1、细叶远志皂苷)肠吸收参数（Ka、Papp、Q）和生物利用度的影响，探究石菖蒲是否可以促进三种成分的肠吸收；采用脑靶向参数(Ce、Re、DTI)评价石菖蒲是否能够促进三种皂苷的脑靶向，研究其与肠吸收的相关性；建立全方、缺石菖蒲方肠吸收及脑微透析HPLC-MS指纹图谱，对比色谱峰的缺失，研究肠吸收及入脑化学成分的变化。 本项目实施可从脑靶向性角度揭示定志小丸中石菖蒲"引药上行"作用机理，为该方临床用药科学性提供依据，为复方配伍研究提供新的思路和方法。

人参及远志皂苷类成分具有较好益智活性，但其生物利用度低，难以透过BBB。临床和动物实验均证实定志小丸对老年痴呆症具有较好疗效，石菖蒲中该方中作为“使药”。本项目主要研究该方是否通过配伍使药石菖蒲提高益智皂苷类成分的胃肠吸收及具有脑靶向性，发挥引药上行作用。.项目研究结果如下：.①建立了复方定志小丸的高效液相色谱（HPLC-ELSD）指纹图谱，以及液质联用（HPLC-PDA-MS）分析方法;石菖蒲挥发油的气相色谱质谱联用(GC-MS)分析方法。.②药动学研究结果阐明石菖蒲能够显著提高人参皂苷Rg1、Rb1、Re三种皂苷类成分的生物利用度，促进三种皂苷成分的体内吸收。.③大鼠离体外翻肠囊模型及在体肠吸收研究表明石菖蒲挥发油对可提高人参皂苷Rg1、Rb1、Re三种人参皂苷药物累计吸收量（Q）、吸收速率常数（Ka）以及肠段表观吸收系数（Papp）。.④定志小丸复方及入血入脑成分研究表明，复方及体内吸收主要成分为皂苷类及黄酮类成分，该类成分对乙酰胆碱酯酶有较好抑制活性。.⑤通过脑组织分布研究表明石菖蒲挥发油可显著提高皂苷类成分的脑组织分布,进一步对天然产物小分子进行结构修饰，引入中药“使药”中小分子基团，证实可以发挥“引药上行”的功效。. 本项目实施可从脑靶向性角度揭示定志小丸中石菖蒲“引药上行”作用机理，为该方临床用药科学性提供依据，为复方配伍研究提供新的思路和方法。