基于MDCK-MDR1细胞模型的P-糖蛋白对丹参主要活性成分血脑屏障转运的影响,ACS Chemical Neuroscience

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基于MDCK-MDR1细胞模型的P-糖蛋白对丹参主要活性成分血脑屏障转运的影响
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2023-01-27 , DOI: 10.1021/acschemneuro.2c00757
Jiahao Fang ₁ , Yuzhen He ₁ , Yuhong Cao ₂ , Yiwei Shi ₁ , Hui Wang ₁ , Zhanying Hong ₁ , Yifeng Chai ₁

Affiliation

丹参( S. miltiorrhiza )是一种中药，广泛用于治疗各种中枢神经系统(CNS)疾病。然而，丹参活性成分穿过血脑屏障 (BBB)的机制仍不清楚。本研究的目的是阐明丹参的四种成分的作用机制，即隐丹参酮 (CTS)、二氢丹参酮 I (DTS I)、丹参酮 IIA (TS IIA) 和原儿茶酸 (PCTA) 使用体外模型穿过 BBB。使用 MDCK-MDR1 单层测试可检测成分的双向传输。高效液相色谱与三重四极杆质谱联用 (HPLC-QQQ/MS) 用于检测通过 BBB 运输的丹参单体成分的含量变化。CTS、DTS I、TS IIA在吸收方向的P _app均低于1.0 × 10 ^–6cm/s，表明这些成分吸收不良，而 PCTA 通过 BBB 适度吸收。CTS、DTS I、TS IIA 和 PCTA 的外排比 (ER) 分别为 1.65、0.92、4.27 和 1.48。P-gp 抑制剂 tariquidar 治疗后，CTS、DTS I 和 TS IIA 的外排比（ER）显着下降，分别为 1.65 至 1.27、0.92 至 0.36 和 4.27 至 0.86（P< 0.05)，而 PCTA 的流出比从 1.48 下降到 0.80，但没有显着性。这表明 CTS、DTS I 和 TS IIA 的转运可能与 P-gp 有关。由于 TS IIA 和 CTS 的 ER 大于 1.5，TS IIA 和 CTS 被验证为四种成分中 P-gp 的底物。对于PCTA和DTS I，它们的转运机制可能与其他转运蛋白或被动转运有关。我们目前的工作中通过分子对接证实了结果。本研究建立了体外血脑屏障模型，并将其应用于丹参活性成分的反式血脑屏障研究为首次研究，为进一步研究其他中药治疗中枢神经系统疾病的作用机制提供依据，对促进中药的合理有效使用具有重要意义。

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Effect of P-Glycoprotein on the Blood–Brain Barrier Transport of the Major Active Constituents of Salvia miltiorrhiza Based on the MDCK-MDR1 Cell Model

Salvia miltiorrhiza Bunge (S. miltiorrhiza) is a traditional Chinese medicine that has been widely used in the treatment of various central nervous system (CNS) diseases. However, the mechanism of active components of S. miltiorrhiza crossing the blood–brain barrier (BBB) stays unclear. The purpose of this study was to clarify the mechanism of four ingredients of S. miltiorrhiza, i.e., cryptotanshinone (CTS), dihydrotanshinone I (DTS I), tanshinone IIA (TS IIA), and protocatechuic acid (PCTA) crossing the BBB using the in vitro model. The bidirectional transport of detectable components was tested using the MDCK-MDR1 monolayers. High performance liquid chromatography coupled to triple-quadrupole mass spectrometry (HPLC-QQQ/MS) was used to detect the content changes of S. miltiorrhiza monomer components transported through the BBB. P_app of CTS, DTS I, and TS IIA in the absorption direction were lower than 1.0 × 10^–6 cm/s, suggesting that these components were poorly absorbed, while PCTA was moderately absorbed through the BBB. The efflux ratio (ER) of CTS, DTS I, TS IIA, and PCTA were 1.65, 0.92, 4.27, and 1.48, respectively. After treatment with P-gp inhibitor tariquidar, the efflux ratio (ER) of CTS, DTS I, and TS IIA significantly decreased from 1.65 to 1.27, 0.92 to 0.36, and 4.27 to 0.86 (P < 0.05), respectively, while the efflux ratio of PCTA decreased without significance from 1.48 to 0.80. This indicated that the transport of CTS, DTS I, and TS IIA might be related to P-gp. TS IIA and CTS were verified as the substrates of P-gp among the four components since the ER of TS IIA and CTS is greater than 1.5. For PCTA and DTS I, their transport mechanism may be related to other transport proteins or passive transport. The results were confirmed by molecular docking in our current work. In this study, an in vitro BBB model was established and applied to the trans-BBB study of active components in S. miltiorrhiza for the first time, which may provide a basis for further research on the mechanisms of other TCMs in treating CNS diseases and is of great significance in promoting the rational and effective use of TCMs.

更新日期：2023-01-27

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