The Blood-Brain Barrier Permeability of Six Indole Alkaloids from Uncariae Ramulus Cum Uncis in the MDCK-pHaMDR Cell Monolayer Model

• Published in: Molecules (Basel, Switzerland) Switzerland), 2017-11, Vol.22 (11), p.1944
• Main Authors: Zhang, Yi-Nan, Yang, Yan-Fang, Xu, Wei, Yang, Xiu-Wei
• Format: Article
• Language: English
• Subjects: Alkaloids; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Calibration; Cell Survival - drug effects; Central nervous system; Chromatography, High Pressure Liquid; Dogs; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacology; Efflux; High performance liquid chromatography; Indole alkaloids; Indole Alkaloids - chemistry; Indole Alkaloids - pharmacology; Indoles; Liquid chromatography; Madin Darby Canine Kidney Cells; MDCK-pHaMDR cell monolayer model; Membrane permeability; Models, Biological; Molecular docking; Molecular Docking Simulation; Monolayers; Nervous system; P-Glycoprotein; Permeability; Pharmacology; Reference Standards; Reproducibility of Results; Rhodamine 123 - metabolism; Rubiaceae; Time Factors; Transport; Uncariae Ramulus Cum Uncis; Verapamil; Verapamil - pharmacology
• ISSN: 1420-3049; 1420-3049
• 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.