The mechanism of the opening of the blood–brain barrier by borneol: A pharmacodynamics and pharmacokinetics combination study

冰片 药理学 血脑屏障 药代动力学 Abcg2型 海马体 P-糖蛋白 体内 中枢神经系统 ATP结合盒运输机 化学 医学 生物 内分泌学 多重耐药 运输机 病理 生物化学 遗传学 中医药 替代医学 抗生素 基因
作者
Bin Yu,Min Ruan,Xiao‐Ping Dong,Yun Yu,Haibo Cheng
出处
期刊:Journal of Ethnopharmacology [Elsevier]
卷期号:150 (3): 1096-1108 被引量:81
标识
DOI:10.1016/j.jep.2013.10.028
摘要

Borneol is widely used in traditional Chinese medicine to facilitate the distribution of central nervous system (CNS) drugs in brain due to its ability to open blood-brain barrier (BBB), however, the underlying mechanism is still unclear. In this study, the effect of borneol on different brain regions were investigated to explore the mechanism.After oral administration of borneol (0.1, 0.2 g/kg) for seven consecutive days, SD rats were injected with Rh123 (1.0 mg/kg). The concentrations of Rh123 were detected in four brain regions of cortex, hippocampus, hypothalamus and striatum by a small animal vivo imaging system and a fluorescence microplate reader respectively. The ultrastructures of BBB were examined. Moreover, the expressions of the four transporters of ATP-binding cassette (ABC) family, multidrug resistance 1a (Mdr1a), multidrug resistance 1b (Mdr1b), multidrug resistance protein 1 (Mrp1), Mrp4, Mrp5 and breast cancer resistance protein (Bcrp) in the four brain regions were analyzed. Finally, the deliveries of borneol in the plasma and the four brain regions were examined by a pharmacokinetics study.Administration of 0.2 g/kg borneol produced loose structure in the tight junction and void structure between the endothelial cell and mesangial cell. Borneol at 0.1 g/kg and 0.2 g/kg increased the delivery of Rh123 in hippocampus and hypothalamus obviously. Permeability index followed a similar trend. Protein expression assays showed that borneol decreased the expression of Mdr1 and Mrp1 in hippocampus and hypothalamus. Further RT-PCR study showed that borneol decreased the expressions of both Mdr1a and Mdr1b in hippocampus and hypothalamus. The pharmacokinetics study demonstrated that the delivery of borneol in cortex was the most and that in striatum the least, with the deliveries of borneol in hippocampus and hypothalamus in between.Borneol showed tissue specific BBB-opening effect, which was associated with its regulation of the ultrastructure of brain tissues and the expressions of Mdr1a, Mdr1b and Mrp1. The present study indicated that borneol should be used in concert with drugs targeting hippocampus or hypothalamus to exert its synergistic effect to the maximum.

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