Abstract
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.
Highlights
The blood brain barrier (BBB) consisting of brain microvascular endothelial cells (BMECs) sealed together by continuous tight junctions plays a pivotal role to control the transportation of substances from blood to brain parenchyma and maintain brain microenvironment homeostasis [1]
Our study demonstrates that borneol could down-regulate mdr1a mRNA levels at 30 min to 4 h after treatment (Figure 4A), and borneol cannot change the levels of mdr2 mRNA
We demonstrated that borneol depressed mdr1a mRNA and P-gp expression, and borneol activated nuclear factor-κB (NF-κB) signaling transiently which peaked at 30 min and returned to control levels within 120 min after treatment (Figure 5A,B)
Summary
The blood brain barrier (BBB) consisting of brain microvascular endothelial cells (BMECs) sealed together by continuous tight junctions plays a pivotal role to control the transportation of substances from blood to brain parenchyma and maintain brain microenvironment homeostasis [1]. P-glycoprotein (P-gp) and multidrug resistance-associated proteins have been shown to be expressed in BMECs, which can transport many physiological and pharmacological substances from the brain to the blood [2,3,4]. Borneol could improve the known P-gp substrates, verapamil and digoxin, transport through the in vitro BBB model (Figure 3C,D). These data suggested that borneol could down-regulate P-gp efflux function and enhance P-gp substrates transport across BBB. We demonstrated that borneol depressed mdr1a mRNA and P-gp expression, and borneol activated NF-κB signaling transiently which peaked at 30 min and returned to control levels within 120 min after treatment (Figure 5A,B). Further experiments to measure the multifactorial pathways of borneol on other substances especially Chinese materia medica across BBB in vivo would be clinically important
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