Abstract
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 1–6, as well as better understanding of their central nervous system pharmacological activities.
Highlights
Uncariae Ramulus Cum Uncis (URCU), the dried hook-bearing branch of Uncaria rhynchophylla (Miq.) Miq. ex Havil., U. macrophylla Wall., U. hirsuta Havil., U. sinensis (Oliv.) Havil. or U. sessilifructusRoxb. [1], has been used as a traditional Chinese medicine (TCM)—called Gou-Teng, in Chinese—for thousands of years
It has been reported that alkaloids 1–5 exhibit inhibitory activity on lipopolysaccharide-induced NO release on microglial cells [4,5], alkaloids 1, 2, 4–6 could protect against glutamate-induced cell death on PC12 cells or cultured cerebellar granule cells [6,7], and that alkaloid 2 could attenuate the Aβ25–35 -induced neuronal apoptosis in hippocampus and ameliorate cognitive deficits [8]
The integrity of differentiated MDCK-pHaMDR cell monolayers was validated before transport
Summary
Uncariae Ramulus Cum Uncis (URCU), the dried hook-bearing branch of Uncaria rhynchophylla (Miq.) Miq. ex Havil., U. macrophylla Wall., U. hirsuta Havil., U. sinensis (Oliv.) Havil. or U. sessilifructusRoxb. (family Rubiaceae) [1], has been used as a traditional Chinese medicine (TCM)—called Gou-Teng, in Chinese—for thousands of years. URCU has been prescribed in many formulas to treat hypertension, headache, epilepsy, senile dementia and eye diseases [2]. Alkaloids are the predominant pharmacologically active components of URCU, and more than 120 alkaloids have been isolated and identified from it [3]. Rhynchophylline (1), isorhynchophylline (2), corynoxeine (3), isocorynoxeine (4), hirsutine (5), and hirsuteine (6) (Figure 1) are representative indole alkaloids from URCU. It has been reported that alkaloids 1–5 exhibit inhibitory activity on lipopolysaccharide-induced NO release on microglial cells [4,5], alkaloids 1, 2, 4–6 could protect against glutamate-induced cell death on PC12 cells or cultured cerebellar granule cells [6,7], and that alkaloid 2 could attenuate the Aβ25–35 -induced neuronal apoptosis in hippocampus and ameliorate cognitive deficits [8].
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