School of Life Sciences, Inner Mongolia University, Hohhot, 010070, China.
J Ethnopharmacol. 2022 Mar 1;285:114837. doi: 10.1016/j.jep.2021.114837. Epub 2021 Nov 14.
The stems of Ephedra sinica and the fruits of Terminalia chebula are combined using in traditional Mongolian medicine formula "Gurigumu-7" for liver diseases. E. sinica stems contains ephedrine with broncho-dilatory activity. However, ephedrine can pass through the blood-brain barrier (BBB) and excite the central nervous system (CNS) to cause insomnia and restlessness.
The present study was to investigate the structures and bioactivities of new compounds formed in vivo after co-administration of E. sinica stems and T. chebula fruits.
Pharmacokinetic investigation was carried out in rats. A parallel artificial membrane permeability measurement system was used to determine BBB permeability. Ex vivo experiments using tracheal rings of guinea pig was performed to examine the tracheal relaxation effect. In vivo hepatoprotective tests were carried out in Tg (fabp10a: dsRed) liver transgenic zebrafish. The fluorescent probe, 2,7-dichlorodihydrofluorescein diacetate, was used to measure reactive oxygen species, and UHPLC-MS was used to determine glutathione concentrations after derivatization with N-ethylmaleimide.
New ephedrine derivatives (1 and 2) formed in vivo and reached their maximum serum concentrations at 0.5 h after administration of the two herbal drugs. Compounds 1 and 2 showed lower BBB permeability than ephedrine, suggesting that they have less adverse effects on the CNS. Compounds 1 and 2 relaxed the tracheal rings and had strong hepatoprotective effect on transgenic zebrafish with liver specific expression of RFP. Compounds 1 and 2 significantly reduced the level of reactive oxygen species while increasing that of glutathione in thioacetamide-treated zebrafish, which might be the hepatoprotective mechanism.
These results provided evidences that the chemical constituents in various herbal drugs in a medicinal formula can interact to generate new compounds with fewer side effects and increased or additive bioactivity.
在传统蒙药“古日古木-7”中，麻黄的茎和诃子的果实合用治疗肝病。麻黄茎含有具有支气管扩张作用的麻黄碱。然而，麻黄碱可以穿透血脑屏障（BBB）并兴奋中枢神经系统（CNS），导致失眠和不安。
本研究旨在研究麻黄茎和诃子果实合用后体内形成的新化合物的结构和生物活性。
在大鼠中进行药代动力学研究。使用平行人工膜渗透测量系统测定 BBB 渗透性。使用豚鼠气管环进行离体实验，以检查气管松弛作用。在 Tg（fabp10a：dsRed）肝脏转基因斑马鱼中进行体内保肝试验。使用荧光探针 2,7-二氯二氢荧光素二乙酸酯测量活性氧，并用 N-乙基马来酰亚胺衍生化后用 UHPLC-MS 测定谷胱甘肽浓度。
体内形成的新麻黄碱衍生物（1 和 2）在两种草药给药后 0.5 h 达到血清浓度峰值。化合物 1 和 2 的 BBB 渗透性低于麻黄碱，表明它们对 CNS 的不良反应较小。化合物 1 和 2 松弛了气管环，对肝脏特异性表达 RFP 的转基因斑马鱼具有很强的保肝作用。化合物 1 和 2 可显著降低硫代乙酰胺处理的斑马鱼中活性氧的水平，同时增加谷胱甘肽的水平，这可能是其保肝机制。
这些结果提供了证据表明，方剂中各种草药的化学成分可以相互作用，产生副作用更少、生物活性增加或具有相加作用的新化合物。
