Chuanxiong Renshen Decoction Inhibits Alzheimer’s Disease Neuroinflammation by Regulating PPARγ/NF-κB Pathway

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-07-24 DOI:10.2147/dddt.s462266

Jinling Hou, Xiaoyan Wang, Jian Zhang, Zhuojun Shen, Xiang Li, Yuanxiao Yang

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Abstract

Background and Aim: Previous studies of our research group have shown that Chuanxiong Renshen Decoction (CRD) has the effect of treating AD, but the exact mechanism of its effect is still not clarified. The aim of this study was to investigate the effect and mechanism of CRD on AD neuroinflammation.
Materials and Methods: Morris Water Maze (MWM) tests were employed to assess the memory and learning capacity of AD mice. HE and Nissl staining were used to observe the neural cells of mice. The expression of Iba-1 and CD86 were detected by immunohistochemical staining. Utilize UHPLC-MS/MS metabolomics techniques and the KEGG to analyze the metabolic pathways of CRD against AD. Lipopolysaccharide (LPS) induced BV2 microglia cells to construct a neuroinflammatory model. The expression of Iba-1 and CD86 were detected by immunofluorescence and flow cytometry. The contents of TNF-α and IL-1β were detected by ELISA. Western blot assay was used to detect the expression of PPARγ, p-NF-κB p65, NF-κB p65 proteins and inflammatory cytokines iNOS and COX-2 in PPARγ/NF-κB pathway with and without PPARγ inhibitor GW9662.
Results: CRD ameliorated the learning and memory ability of 3×Tg-AD mice, repaired the damaged nerve cells in the hippocampus, reduced the area of Iba-1 and CD86 positive areas in both the hippocampus and cortex regions, as well as attenuated serum levels of IL-1β and TNF-α in mice. CRD-containing serum significantly decreased the expression level of Iba-1, significantly reduced the levels of TNF–α and IL-1β, significantly increased the protein expression of PPARγ, and significantly decreased the proteins expression of iNOS, COX-2 and p-NF-κB p65 in BV2 microglia cells. After addition of PPARγ inhibitor GW9662, the inhibitory effect of CRD-containing serum on NF-κB activation was significantly weakened.
Conclusion: CRD can activate PPARγ, regulating PPARγ/NF-κB signaling pathway, inhibiting microglia over-activation and reducing AD neuroinflammation.

Keywords: Alzheimer’disease, Chuanxiong Renshen Decoction, UHPLC-MS/MS, neuroinflammation, PPARγ

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川芎人参汤通过调节 PPARγ/NF-κB 通路抑制阿尔茨海默病神经炎症

背景和目的：本课题组既往研究表明，川芎人参汤（CRD）具有治疗AD的作用，但其确切作用机制尚未明确。本研究旨在探讨川芎人参汤对AD神经炎症的作用及其机制：采用莫里斯水迷宫（MWM）测试评估AD小鼠的记忆和学习能力。HE和Nissl染色用于观察小鼠的神经细胞。通过免疫组化染色检测Iba-1和CD86的表达。利用UHPLC-MS/MS代谢组学技术和KEGG分析CRD防治AD的代谢途径。利用脂多糖（LPS）诱导 BV2 小胶质细胞构建神经炎症模型。免疫荧光和流式细胞术检测了Iba-1和CD86的表达。酶联免疫吸附法检测 TNF-α 和 IL-1β 的含量。采用 Western 印迹法检测 PPARγ、p-NF-κB p65、NF-κB p65 蛋白和炎性细胞因子 iNOS 和 COX-2 在 PPARγ/NF-κB 通路中的表达，并检测是否使用 PPARγ 抑制剂 GW9662：结果：CRD改善了3×Tg-AD小鼠的学习和记忆能力，修复了海马受损的神经细胞，减少了海马和大脑皮层中Iba-1和CD86阳性区域的面积，并降低了小鼠血清中IL-1β和TNF-α的水平。含 CRD 的血清能显著降低 Iba-1 的表达水平，显著降低 TNF-α 和 IL-1β 的水平，显著增加 PPARγ 的蛋白表达，显著降低 BV2 小胶质细胞中 iNOS、COX-2 和 p-NF-κB p65 蛋白的表达。加入 PPARγ 抑制剂 GW9662 后，含 CRD 血清对 NF-κB 激活的抑制作用明显减弱：结论：CRD可激活PPARγ，调节PPARγ/NF-κB信号通路，抑制小胶质细胞过度激活，减轻AD神经炎症：阿尔茨海默病川芎人参汤超高效液相色谱-质谱联用神经炎症 PPARγ

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.