P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice
P-glycoprotein Inhibitor Tariquidar Potentiates Efficacy of Astragaloside IV in Experimental Autoimmune Encephalomyelitis Mice
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P-糖蛋白抑制剂 Tariquidar 增强黄芪甲苷 IV 对实验性自身免疫性脑脊髓炎小鼠的疗效
DOI：
10.3390/molecules24030561
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发表时间：
2019-02
期刊：
影响因子：
4.6
通讯作者：
Wu Xiaojun
中科院分区：
文献类型：
--
作者：
Zhang Wei;Liu Mei;Yang Liu;Huang Fei;Lan Yunyi;Li Hongli;Wu Hui;Zhang Beibei;Shi Hailian;Wu Xiaojun
ATP结合盒（ABC）转运蛋白，如P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP），经常降低药物疗效，是耐药的主要原因。黄芪甲苷（ASIV）是从黄芪中提取的具有生物活性的皂苷之一，在多发性硬化（MS）动物模型小鼠中已被证明可以减轻实验性自身免疫性脑脊髓炎（EAE）的进展。在本研究中，我们首次发现ASIV诱导EAE小鼠中枢神经系统（CNS）微血管内皮细胞中P-gp和BCRP的上调。进一步的研究发现，作为P-gp抑制剂的tariquidar可促进ASIV向CNS的渗透。在小鼠脑微血管内皮细胞系bEnd.3细胞上，tariquidar有利于ASIV的净摄取和转运。进一步的分子对接实验表明ASIV可能是P-gp的潜在底物。在EAE小鼠中，tariquidar被证明可以增强ASIV的功效，如通过减轻临床症状和降低发病率以及减轻CNS中的炎性浸润和减少脱髓鞘所示。因此，P-gp抑制剂可以提高ASIV对EAE小鼠的治疗效果，这可能会促进ASIV在MS治疗中的临床应用。
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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DOI：
10.1186/s13046-018-0878-0
发表时间：
2018-08-29
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
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通讯作者：
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影响因子：
5.3
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通讯作者：
Guzen FP
影响因子：
5.5
作者：
Liu, Wei-Ye;Wang, Zhi-Bin;Li, Ling
通讯作者：
Li, Ling
影响因子：
3.8
作者：
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影响因子：
5.4
作者：
Lou, Yanmei;Guo, Zhenzhen;Wu, Jinjun
通讯作者：
Wu, Jinjun