Borneol Depresses P-Glycoprotein Function by a NF-κB Signaling Mediated Mechanism in a Blood Brain Barrier in Vitro Model.
Borneol Depresses P-Glycoprotein Function by a NF-κB Signaling Mediated Mechanism in a Blood Brain Barrier in Vitro Model.
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DOI：
10.3390/ijms161126051
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发表时间：
2015-11-18
影响因子：
5.6
通讯作者：
Gao X
中科院分区：
文献类型：
--
作者：
Fan X;Chai L;Zhang H;Wang Y;Zhang B;Gao X
构成血脑屏障（BBB）的脑微血管内皮细胞（BMECs）上的P - 糖蛋白（P - gp）影响血液和大脑之间物质的运输。本研究的目的是表征冰片对血脑屏障上P - gp外排功能的影响，并探索其潜在机制。我们建立了一个由大鼠脑微血管内皮细胞和星形胶质细胞组成的体外血脑屏障模型，以测量冰片对已知的P - gp底物跨血脑屏障运输的影响，并检测脑微血管内皮细胞中P - gp的功能和表达以及调节P - gp表达的信号通路。冰片增加了罗丹明123在细胞内的积累，增强了维拉帕米和地高辛在体外血脑屏障模型中的跨膜运输，并降低了mdr1a mRNA和P - gp的表达。冰片可激活核因子 - κB（NF - κB），而用MG132（苄氧羰基 - 亮氨酸 - 亮氨酸 - 亮氨酸醛）和SN50（一种抑制性肽）抑制NF - κB可消除冰片诱导的P - gp降低。这些数据表明，在体外血脑屏障模型中，冰片通过NF - κB信号介导的机制降低脑微血管内皮细胞中P - gp的功能。
P-glycoprotein (P-gp) on brain microvascular endothelial cells (BMECs) that form the blood brain barrier (BBB), influences transportation of substances between blood and brain. The objective of this study was to characterize the effects of borneol on P-gp efflux function on BBB and explore the potential mechanisms. We established an in vitro BBB model comprised of rat BMECs and astrocytes to measure the effects of borneol on the known P-gp substrates transport across BBB, and examined the function and expression of P-gp in BMECs and the signaling pathways regulating P-gp expression. Borneol increased intracellular accumulation of Rhodamine 123, enhanced verapamil and digoxin across the BBB in vitro model, and depressed mdr1a mRNA and P-gp expression. Borneol could activate nuclear factor-κB (NF-κB) and inhibition of NF-κB with MG132 (carbobenzoxy-Leu-Leu-leucinal) and SN50 (an inhibitory peptide) obscuring the P-gp decreases induced by borneol. These data suggested that borneol depresses P-gp function in BMECs by a NF-κB signaling medicated mechanism in a BBB in vitro model.