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

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
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Molecules 2017, 22(11), 1944; https://doi.org/10.3390/molecules22111944
Received: 14 October 2017 / Revised: 8 November 2017 / Accepted: 9 November 2017 / Published: 10 November 2017
(This article belongs to the Section Natural Products Chemistry)
Uncariae Ramulus Cum Uncis (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 (Papp) were calculated. Among the six alkaloids, isorhynchophylline (2), isocorynoxeine (4), hirsutine (5) and hirsuteine (6) showed high permeability, with Papp values at 10−5 cm/s level in bidirectional transport. For rhynchophylline (1) and corynoxeine (3), they showed moderate permeability, with Papp values from the apical (AP) side to the basolateral (BL) side at 10−6 cm/s level and efflux ratio (Papp BL→AP/Papp AP→BL) above 2. The time- and concentration-dependency experiments indicated that the main mechanism for 2, 4, 5 and 6 through BBB was passive diffusion. The efflux mechanism involved in the transports of compounds 1 and 3 could be reduced significantly by verapamil, and molecular docking screening also showed that 1 and 3 had strong bindings to P-glycoprotein. This study provides useful information for predicting the BBB permeability for 16, as well as better understanding of their central nervous system pharmacological activities. View Full-Text
Keywords: Uncariae Ramulus Cum Uncis; Rubiaceae; Indole alkaloids; MDCK-pHaMDR cell monolayer model; Blood-brain barrier; Permeability Uncariae Ramulus Cum Uncis; Rubiaceae; Indole alkaloids; MDCK-pHaMDR cell monolayer model; Blood-brain barrier; Permeability
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Zhang, Y.-N.; Yang, Y.-F.; Xu, W.; Yang, X.-W. The Blood-Brain Barrier Permeability of Six Indole Alkaloids from Uncariae Ramulus Cum Uncis in the MDCK-pHaMDR Cell Monolayer Model. Molecules 2017, 22, 1944.

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