丹参素冰片酯脑靶向作用及其对血脑屏障上P-糖蛋白的影响

发布时间：2018-02-22 02:52

  本文关键词： 丹参素 冰片 前药 脑靶向 P-糖蛋白　出处：《合肥工业大学》2017年硕士论文　论文类型：学位论文

【摘要】：丹参素(Danshensu,DSS)具有治疗缺血性心脑血管疾病的药理活性,但其易氧化、化学性质不稳定、体内半衰期短、脑部靶向性也有待加强。血脑屏障通透性增加及P-糖蛋白(P-gp)外排功能抑制均有助于提高药物脑靶向性。已有研究报道,丹参-冰片合用,能提高丹参素的脑部分布。为此,本文将具有血脑屏障促透及P-gp抑制作用的冰片作为载体引入丹参素,设计了一系列丹参素-冰片酯类前药,通过对这些分子脑靶向相关参数预测、筛选,确定了目标分子,并进行目标分子及丹参素-冰片联合用药脑靶向作用研究,研究结果如下:(1)采用计算软件对丹参素-冰片酯类分子的筛选结果表明:丹参素冰片酯(Danshensu Broneol ester,DBE)可能具有潜在脑靶向作用。对设计的6个丹参素-冰片酯类分子(DB1-DB6)进行了脂水分配系数(logP)、脑血浓度比(BB)预测及P-gp亲和力,并结合合成难易分析,我们选择DBE(代号DB1)作为目标分子进行合成及后续体内靶向性评价。(2)前药DBE及丹参素钠-冰片(Sodium Danshensu-borneol,SDSS-B)联合用药均表现出明显的脑靶向作用,DBE治疗有效指数(therapeutic availability,TA)和脑靶向指数(drug targeting index,DTI)优于联合用药。建立了DSS在大鼠血浆和脑匀浆的HPLC定量检测方法,采用该方法研究了大鼠尾静脉注射SDSS、DBE及SDSS-B药代动力学。DBE在大鼠血浆中药代动力学参数得以改善,其分解得到DSS的t1/2、MRT0-∞相比SDSS分别增加了1.76、1.71倍。同时,DBE及SDSS-B在大鼠脑内检测到DSS的脑部吸收量明显增加;MRT0-∞分别为直接注射SDSS的2.71倍和1.42倍,DBE相比SDSS-B更能显示出长效缓释特性。SDSS-B和DBE的TA分别为3.39和4.15;DTI分别为3.63和9.93。(3)DBE脑靶向性强于SDSS-B,这与其有效抑制P-gp表达和外排转运功能有关。通过大鼠给药后脑组织海马区P-gp的蛋白免疫印迹检测结果表明:与溶媒控制组相比,SDSS仅在30min时对P-gp表达有抑制作用;DBE和SDSS-B除给药5 min外,在其它给药间隔均可显著降低大鼠海马组织中P-gp表达量(P0.01)。在给药45 min时,DBE及SDSS-B组的P-gp表达量均处于最低水平,分别达到47.58%和46.54%;随着给药时间延长至60 min,DBE对P-gp表达的抑制作用强于SDSS-B(85.04%vs.95.29%)。以罗丹明123作为底物对大鼠给予SDSS、DBE、SDSS-B的P-gp外排功能检测结果表明:与SDSS给药相比,SDSS-B联合给药和DBE前药在给药后各时间的脑组织中Rho123浓度均呈现增加趋势,对应的Kp值也分别增至1.26~4倍和1.38~5.4倍。在四个给药时刻,SDSS-B及DBE均能抑制大鼠脑部P-gp外排功能,以DBE的抑制作用更强。
[Abstract]:Danshensuang DSSs has pharmacological activity in treating ischemic cardiovascular and cerebrovascular diseases, but it is easy to be oxidized, unstable in chemical properties, and has a short half-life in vivo. The enhancement of blood-brain barrier permeability and the inhibition of P-gp efflux function can improve the drug's brain targeting. It has been reported that the combination of Danshen and Borneol can improve the brain distribution of Danshensu. In this paper, borneol with blood-brain barrier penetration and P-gp inhibition was introduced into Danshensu. A series of Danshensin-borneol prodrugs were designed. The target molecules and the brain targeting effect of Danshensu combined with borneol were studied. The results are as follows: (1) the screening results of Danshensu borneol ester molecules by computer software show that Danshensu Broneol estersterol DBE) may have a potential brain targeting effect on the design of six Danshensin-borneol ester molecules (danshensu Broneol ester-DB6). The prediction of lipid water partition coefficient (log P), brain blood concentration ratio (BBB) and P-gp affinity were carried out. And combined with the difficult and easy analysis of synthesis, We selected DBE (code name DB1) as target molecule to synthesize and evaluate in vivo targeting ability of DBE) prodrug DBE and sodium Danshensu-borneoln SDSS-B both showed obvious brain targeting effect and DBE showed significant therapeutic effect on efficacy index of therapeutic efficacy and availability of brain target TA) and brain target drugs such as Danshensu-borneolium SDSS-B). The index drug targeting index (DTI) was superior to that of combined drug therapy. A HPLC quantitative method for the detection of DSS in plasma and brain homogenate of rats was established. This method was used to study the improvement of plasma pharmacokinetic parameters of SDSS-dae and SDSS-B pharmacokinetics in rats. Compared with SDSS, the t 1 / 2% MRT0- 鈭，

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