Highlights
- •P-glycoprotein restricts numerous therapeutic drugs across blood-brain barrier.
- •P-glycoprotein inhibitors increase brain accumulation of therapeutic drugs.
- •P-glycoprotein inhibitors have been disappointing because of side effects.
- •Z-guggulsterone might regulate P-glycoprotein expression at blood-brain barrier.
Abstract
The present study was to investigate whether Z-guggulsterone had the regulatory effect on the activity and expression of P-glycoprotein
in rat brain microvessel endothelial cells (rBMECs) and in rat brain. Inorganic phosphate
liberation assay, high performance liquid chromatography, and western blot analysis
were performed to assess the P-glycoprotein ATPase activity, the accumulation of NaF
and rhodamine 123, and P-glycoprotein and MRP1 expression. The results showed that
Z-guggulsterone (0–100 μM) significantly enhanced basal P-glycoprotein ATPase activity in a concentration-dependent
manner. Tetrandrine (0.1, 0.3, 1 μM) or cyclosporine A (0.1, 0.3, 1 μM) had non-competitively inhibitory manner on Z-guggulsterone-stimulated P-glycoprotein ATPase activity, suggesting that Z-guggulsterone might have unique binding site or regulating site on P-glycoprotein.
However, Z-guggulsterone (30, 100 μM) had almost no influence on MRP1 expression in rBMECs. Further results revealed
that Z-guggulsterone (50 mg/kg) significantly increased the accumulation of rhodamine 123 by down-regulating
P-glycoprotein expression in rat brain, as compared with control (P < 0.05). Our studies suggested that Z-guggulsterone potentially inhibited the activity and expression of P-glycoprotein
in rBMECs and in rat brain.
Keywords
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Article info
Publication history
Published online: February 20, 2016
Accepted:
February 18,
2016
Received in revised form:
February 5,
2016
Received:
January 7,
2016
Identification
Copyright
© 2016 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
