P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice.

Abstract

ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), often reduce drug efficacy and are the major cause of drug resistance. Astragaloside IV (ASIV), one of the bioactive saponins isolated from Astragalus membranaceus, has been demonstrated to alleviate the progression of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for multiple sclerosis (MS). In the present study, we found for the first time that ASIV induced the upregulation of P-gp and BCRP in the central nervous system (CNS) microvascular endothelial cells of EAE mice. Further study disclosed that tariquidar, a P-gp inhibitor, could facilitate the penetration of ASIV into CNS. On bEnd.3 cells, a mouse brain microvascular endothelial cell line, tariquidar benefited the net uptake and transport of ASIV. Additional molecular docking experiment suggested that ASIV might be a potential substrate of P-gp. In EAE mice, tariquidar was demonstrated to enhance the efficacy of ASIV, as shown by attenuated clinical symptom and reduced incidence rate as well as mitigated inflammatory infiltration and decreased demyelination in the CNS. Collectively, our findings implicate that P-gp inhibitor can promote the therapeutic efficacy of ASIV on EAE mice, which may boost its clinical usage together with ASIV in the therapy of MS.

• Authors: Wei Zhang, Mei Liu, Liu Yang, Fei Huang, Yunyi Lan, Hongli Li, Hui Wu, Beibei Zhang, Hailian Shi, Xiaojun Wu
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 24 Issue 3 (Feb 03 2019) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 30717494 (Publication Type: Journal Article)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Abcg2 protein, mouse
• Quinolines
• Saponins
• Triterpenes
• astragaloside A
• tariquidar

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (genetics, metabolism)
• Animals
• Blood-Brain Barrier
• Cell Line
• Drug Synergism
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology, metabolism)
• Endothelial Cells (drug effects, metabolism)
• Female
• Mice
• Molecular Conformation
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Quinolines (chemistry, metabolism, pharmacokinetics)
• Saponins (chemistry, metabolism, pharmacology)
• Substrate Specificity
• Triterpenes (chemistry, metabolism, pharmacology)