State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing 100191, China.
Molecules. 2017 Nov 10;22(11):1944. doi: 10.3390/molecules22111944.
(URCU) is a widely used traditional Chinese medicine, and is reported to have various central nervous system effects. Alkaloids have been demonstrated to be the predominant pharmacological active components of URCU. In order to evaluate the blood-brain barrier (BBB) permeability and transport mechanism of six typical indole alkaloids from URCU, the MDCK-pHaMDR cell monolayer model was used as an in vitro surrogate model for BBB. The samples were analyzed by high-performance liquid chromatography, and the apparent permeability coefficients () were calculated. Among the six alkaloids, isorhynchophylline (), isocorynoxeine (), hirsutine () and hirsuteine () showed high permeability, with values at 10 cm/s level in bidirectional transport. For rhynchophylline () and corynoxeine (), they showed moderate permeability, with values from the apical (AP) side to the basolateral (BL) side at 10 cm/s level and efflux ratio (/) above 2. The time- and concentration-dependency experiments indicated that the main mechanism for , , and through BBB was passive diffusion. The efflux mechanism involved in the transports of compounds and could be reduced significantly by verapamil, and molecular docking screening also showed that and had strong bindings to -glycoprotein. This study provides useful information for predicting the BBB permeability for -, as well as better understanding of their central nervous system pharmacological activities.
乌头碱（URCU）是一种广泛使用的中药，据报道具有多种中枢神经系统作用。生物碱已被证明是乌头碱的主要药理活性成分。为了评估 6 种典型吲哚生物碱从 URCU 中穿过血脑屏障（BBB）的渗透能力和转运机制，使用 MDCK-pHaMDR 细胞单层模型作为 BBB 的体外替代模型。样品通过高效液相色谱法进行分析，并计算表观渗透系数（）。在这 6 种生物碱中，异乌头碱（）、异去氧乌头碱（）、育亨宾（）和育亨宾碱（）表现出高渗透性，在双向转运中值达到 10 cm/s 水平。对于头碱（）和钩藤碱（），它们表现出中等渗透性，在 10 cm/s 水平的从顶侧（AP）到基底外侧（BL）的方向上值，并且外排比（/）大于 2。时间和浓度依赖性实验表明，、、和通过 BBB 的主要机制是被动扩散。化合物和的转运涉及的外排机制可被维拉帕米显著降低，分子对接筛选也表明和与 -糖蛋白具有很强的结合能力。本研究为预测-的 BBB 渗透性提供了有用的信息，也更好地理解了它们的中枢神经系统药理活性。
