XENOBIOTICA
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2019
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IF 1.902
Siyuan Sun,Sisi Zhou,Shaowei Lei,Shujie Zhu,Kai Wang,Huidi Jiang,Hui Zhou
1. Jatrorrhizine is an active ingredient found in various traditional Chinese medicinal plants. Based on our previous finding that jatrorrhizine was a potent inhibitor of OCT2 and OCT3, the aim of the present study was to explore whether jatrorrhizine has an antidepressant-like action action via inhibition of uptake-2 transporters.2. In vitro uptake tests showed that jatrorrhizine strongly inhibited PMAT-mediated MPP+ uptake with an IC50 value of 1.05 μM and reduced 5-HT and NE uptake mediated by hOCT2, hOCT3 and hPMAT with IC50 values of 0.1–1 μM (for OCT2 and OCT3) and 1–10 μM (for PMAT).3. In mouse synaptosomes, jatrorrhizine suppressed 5-HT and NE uptake in a concentration dependently manner, where the role of uptake-2 inhibition is significant.4. The antidepressant-like action of jatrorrhizine was evaluated by mouse tail suspension test (TST). The TST showed that one week of jatrorrhizine (5, 10 and 20 mg/kg, i.p.) or venlafaxine (20 mg/kg, i.g.) can significantly reduce the duration of immobility when compared with vehicle control group.5. The concentration of jatrorrhizine shows a dose-dependent increase in brain tissues.6. Our study suggested that jatrorrhizine might be used as an antidepressant agent via inhibition of uptake-2 transporters.
研究领域:
药理学
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神经科学
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中医药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Junying Li,Xiaoxiao Shan,Yu Gao,Haizhou Zhu,Hongyan Cheng,Chengjie Xing,Lele Zhou,Wenkang Tao,Yangyang Li,Baoqi Yin,Caiyun Zhang
Ethnopharmacological relevance Kai-Xin-San (KXS) has a significant effect therapeutic on Alzheimer's disease (AD) in clinical practice. According to the compatibility theory of traditional Chinese medicine, Acori Tatarinowii Rhizoma (ATR) serves as the guiding drug in the KXS formulation and is believed to enhance the bioavailability and brain tissue distribution of the other drugs. However, the mechanism underlying the “guiding medicine upwards” effect of ATR in KXS remains unexplored. Aim of the study The aim of this study is to investigate the role of ATR in the efficacy of KXS on amyloid precursor protein/presenilin 1 (APP/PS1) mice, as well as its impact on the brain tissue distribution of other active ingredients in the KXS formula, and to elucidate the mechanism of ATR's “guiding medicine upwards” effect in KXS. Materials and methods The pharmacodynamic effects of ATR in KXS were assessed through behavioral tests, immunohistochemical staining, and Nissl staining. Additionally, the levels of inflammatory factors, as well as the activities of malondialdehyde, superoxide dismutase, and acetylcholinesterase, were measured using enzyme-linked immunosorbent assay kits. Subsequently, the effect of ATR on the ultrastructure of the blood-brain barrier (BBB) in APP/PS1 mice was observed using transmission electron microscopy (TEM), and the pharmacodynamic components of KXS in cerebrospinal fluid were quantified by ultra-high-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MS/MS). Furthermore, Western blot (WB) analysis was used to quantitatively assess the expression of tight junction proteins (Claudin-5, Occludin, and ZO-1) and transporters (OCT3, OATP2, P-gp, and MRP1) in the BBB. Finally, bEND.3 cells and astrocyte cells were co-cultured to validate the effect of ATR on KXS. The expressions of OCT3/OATP2 and P-gp/MRP1 in BBB cell model were determined by WB and the content of pharmacodynamic components in the lower chamber of the transwell were also analyzed by UPLC-MS/MS. Results Behavioral test results suggest that KXS significantly improved the learning and memory capacities of APP/PS1 mice compared to the ATR-free KXS group. Furthermore, KXS was more effective in reducing amyloid-β protein deposition in the brain and repairing damaged neurons in the CA1 and CA3 regions than ATR-free KXS. Notably, KXS significantly reversed the pathological biochemical indices compared to the ATR-free KXS group. These results indicate that ATR has a positive effect on the pharmacodynamics of KXS in treating AD. Most importantly, TEM results revealed that KXS repaired the damaged BBB in AD mice, and ATR contributed to the improvement of BBB integrity. Furthermore, KXS and ATR increased the expression levels of Claudin-5, Occludin, and ZO-1 proteins in AD mice. Meanwhile, the levels of ginsenoside Rg1, ginsenoside Rb1, and polygalaxanthone III in the cerebrospinal fluid of the KXS group were 1.47, 1.39, and 2.02 times higher than those in the ATR-free KXS group, respectively. WB results showed that ATR and KXS significantly upregulated the expression of OCT3/OATP2 uptake transporters and downregulated the expression of P-gp/MRP1 efflux transporters compared to ATR-free KXS. Concurrently, in vitro BBB cell experimental results suggest that ATR promoted the transport of ginsenoside Rg1, ginsenoside Rb1, and polygalaxanthone III across BBB cells in KXS, and the regulation of OCT3/OATP2 and P-gp/MRP1 expression was consistent with the in vivo trends observed in AD mice. Conclusions ATR plays a critical role in enhancing the efficacy of KXS in treating AD and facilitates the entry of other pharmacodynamic components into the brain. The mechanism underlying the “guiding medicine upwards” effect of ATR may involve the regulation of OCT3/OATP2 and P-gp/MRP1 transporters.
研究领域:
民族药理学
·
神经科学
·
中药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）