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

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 demonstrat...

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Autores principales: Zhang, Wei, Liu, Mei, Yang, Liu, Huang, Fei, Lan, Yunyi, Li, Hongli, Wu, Hui, Zhang, Beibei, Shi, Hailian, Wu, Xiaojun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384695/
https://www.ncbi.nlm.nih.gov/pubmed/30717494
http://dx.doi.org/10.3390/molecules24030561
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author Zhang, Wei
Liu, Mei
Yang, Liu
Huang, Fei
Lan, Yunyi
Li, Hongli
Wu, Hui
Zhang, Beibei
Shi, Hailian
Wu, Xiaojun
author_facet Zhang, Wei
Liu, Mei
Yang, Liu
Huang, Fei
Lan, Yunyi
Li, Hongli
Wu, Hui
Zhang, Beibei
Shi, Hailian
Wu, Xiaojun
author_sort Zhang, Wei
collection PubMed
description 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.
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spelling pubmed-63846952019-02-23 P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice Zhang, Wei Liu, Mei Yang, Liu Huang, Fei Lan, Yunyi Li, Hongli Wu, Hui Zhang, Beibei Shi, Hailian Wu, Xiaojun Molecules Article 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. MDPI 2019-02-03 /pmc/articles/PMC6384695/ /pubmed/30717494 http://dx.doi.org/10.3390/molecules24030561 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Wei
Liu, Mei
Yang, Liu
Huang, Fei
Lan, Yunyi
Li, Hongli
Wu, Hui
Zhang, Beibei
Shi, Hailian
Wu, Xiaojun
P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice
title P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice
title_full P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice
title_fullStr P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice
title_full_unstemmed P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice
title_short P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice
title_sort p-glycoprotein inhibitor tariquidar potentiates efficacy of astragaloside iv in experimental autoimmune encephalomyelitis mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384695/
https://www.ncbi.nlm.nih.gov/pubmed/30717494
http://dx.doi.org/10.3390/molecules24030561
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