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李溢涵, 杨萍, 刘红华, 袁宁.基于TLR4/NF-κB/NLRP3信号通路探讨香附挥发油对产后抑郁小鼠的干预作用[J].湖南中医药大学学报,,():[点击复制] |
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| 基于TLR4/NF-κB/NLRP3信号通路探讨香附挥发油对产后抑郁小鼠的干预作用 |
| 李溢涵,杨萍,刘红华,袁宁 |
| (湖南中医药大学临床医学院, 湖南 长沙 410208;湖南省第二人民医院(湖南省脑科医院), 湖南 长沙 410007) |
| 摘要: |
| 目的 评价香附挥发油对产后抑郁（PPD）的干预作用，并探讨其与海马神经炎症及Toll样受体4/核因子κB/NOD样受体热蛋白结构域相关蛋白3（TLR4/NF-κB/NLRP3）信号通路的关系。方法 采用网络药理学预测香附挥发油的潜在作用靶点与富集通路。将雌性C57BL/6小鼠随机分为正常对照组、模型组、香附组和氟西汀组，每组6只。除正常对照组外，其余各组采用激素模拟妊娠后突然停撤法建立PPD模型；正常对照组和模型组灌胃给予生理盐水，香附组灌胃给予香附挥发油50 mg/kg· d，氟西汀组腹腔注射氟西汀10 mg/kg· d，连续干预2周。采用行为学实验评价小鼠抑郁样行为及药物干预效果； HE染色观察小鼠海马组织病理变化； ELISA检测小鼠血清和海马组织中诱导型一氧化氮合酶（iNOS）、环氧合酶-2（COX-2）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和干扰素-γ（IFN-γ）水平；免疫荧光染色检测小鼠海马齿状回区NLRP3和半胱氨酸天冬氨酸蛋白酶-1（Caspase-1）阳性表达； Western blot检测小鼠海马组织Toll样受体4（TLR4）、髓样分化因子88（MyD88）、磷酸化核因子-κB p65/核因子-κB p65（p-p65/p65）、肿瘤坏死因子受体相关因子6（TRAF6）、NLRP3和Caspase-1蛋白表达水平。结果 网络药理学结果显示，香附挥发油相关靶点主要富集于Toll样受体、TNF、NF-κB、NOD样受体等炎症相关信号通路。动物实验结果显示，第0周各组小鼠糖水偏好率、强迫游泳不动时间及悬尾不动时间比较，差异均无统计学意义（P＞0.05）。第5周，与正常对照组比较，模型组小鼠糖水偏好率降低，强迫游泳不动时间和悬尾不动时间延长（P＜0.01）；血清及海马组织中iNOS、COX-2、TNF-α、IL-1β、IFN-γ水平均升高（P＜0.01）；海马齿状回NLRP3和Caspase-1阳性表达升高（P＜0.01）；海马组织TLR4、MyD88、p-p65/p65、TRAF6、NLRP3及Caspase-1蛋白表达水平均升高（P＜0.01）。与模型组比较，香附组和氟西汀组小鼠糖水偏好率升高，强迫游泳不动时间和悬尾不动时间缩短（P＜0.01）；血清及海马组织中iNOS、COX-2、TNF-α、IL-1β、IFN-γ水平均降低（P＜0.01）；海马齿状回NLRP3和Caspase-1阳性表达降低（P＜0.01）；香附组和氟西汀组海马组织TLR4、MyD88、p-p65/p65、TRAF6、NLRP3蛋白表达水平均降低（P＜0.01或P＜0.05），香附组Caspase-1蛋白表达水平降低（P＜0.05），氟西汀组Caspase-1蛋白表达呈下降趋势，但差异无统计学意义（P＞0.05）。结论 香附挥发油可能通过抑制TLR4/NF-κB/NLRP3信号通路介导的海马神经炎症而发挥抗产后抑郁作用，为其作为产后抑郁潜在干预药物提供实验依据。 |
| 关键词: 产后抑郁 香附挥发油 TLR4/NF-κB/NLRP3信号通路 炎症因子 |
| DOI： |
| 投稿时间：2025-12-10 |
| 基金项目:湖南省自然科学基金项目（2023JJ60293，2024JJ9356，2024JJ8139）；湖南省卫健委高层次人才重点科研项目（20230412）；湖南省中医药管理局中医药医院管理项目（B2023133）；湖南省卫生健康委员会科研项目（D202314056707）。 |
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| Intervention effects of Xiangfu (Cyperi Rhizoma) volatile oil on postpartum depression in mice via the TLR4/NF-κB/NLRP3 signaling pathway |
| LI Yihan, YANG Ping, LIU Honghua, YUAN Ning |
| (School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;The Second People's Hospital of Hunan Province (Brain Hospital of Hunan Province), Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To evaluate the intervention effects of Xiangfu (Cyperi Rhizoma) volatile oil on postpartum depression (PPD) and to explore its relationship with hippocampal neuroinflammation and the Toll-like receptor 4/nuclear factor-κB/NOD-like receptor pyrin domain-containing protein 3 (TLR4/NF-κB/NLRP3) signaling pathway. Methods Network pharmacology was used to predict the potential targets and enriched pathways of Xiangfu (Cyperi Rhizoma) volatile oil. Female C57BL/6 mice were randomly divided into normal control group, model group, Xiangfu (Cyperi Rhizoma) volatile oil group, and fluoxetine group, with six mice in each group. Except for the normal control group, PPD models were established in the other groups by abrupt withdrawal of hormones following hormone-simulated pregnancy. The normal control and model groups were given normal saline by gavage, the Xiangfu (Cyperi Rhizoma) volatile oil group received Xiangfu (Cyperi Rhizoma) volatile oil 50 mg/kg·d by gavage, and the fluoxetine group received fluoxetine 10 mg/kg·d intraperitoneally, for two consecutive weeks. Behavioral tests were performed to evaluate depressive-like behaviors and drug intervention effects. HE staining was used to observe hippocampal pathological changes. ELISA was used to determine the levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ) in serum and hippocampal tissue. Immunofluorescence staining was performed to measure the positive expression levels of NLRP3 and cysteinyl aspartate-specific protease-1 (Caspase-1) in the hippocampal dentate gyrus. Western blot was used to determine the protein expression levels of TLR4, myeloid differentiation factor 88 (MyD88), phosphorylated nuclear factor-κB p65/nuclear factor-κB p65 (p-p65/p65), tumor necrosis factor receptor-associated factor 6 (TRAF6), NLRP3, and Caspase-1 in hippocampal tissue. Results Network pharmacology analysis showed that the targets related to Xiangfu (Cyperi Rhizoma) volatile oil were mainly enriched in inflammation-related signaling pathways, including Toll-like receptor, TNF, NF-κB, and NOD-like receptor pathways. In the animal experiments, at week 0, there were no statistically significant differences among groups in sucrose preference rate, forced swimming immobility time, or tail suspension immobility time (P>0.05). At week 5, compared with the normal control group, the model group showed a decreased sucrose preference rate, prolonged forced swimming immobility time and tail suspension immobility time (P<0.01), increased levels of iNOS, COX-2, TNF-α, IL-1β, and IFN-γ in serum and hippocampal tissue (P<0.01), elevated positive expression levels of NLRP3 and Caspase-1 in the hippocampal dentate gyrus (P<0.01), and upregulated protein expression levels of TLR4, MyD88, p-p65/p65, TRAF6, NLRP3, and Caspase-1 in hippocampal tissue (P<0.01). Compared with the model group, both the Xiangfu (Cyperi Rhizoma) volatile oil and fluoxetine groups exhibited increased sucrose preference rate, shortened forced swimming immobility time and tail suspension immobility time (P<0.01), reduced levels of iNOS, COX-2, TNF-α, IL-1β, and IFN-γ in serum and hippocampal tissue (P<0.01), decreased positive expression levels of NLRP3 and Caspase-1 in the hippocampal dentate gyrus (P<0.01), and downregulated protein expression levels of TLR4, MyD88, p-p65/p65, TRAF6, and NLRP3 in hippocampal tissue (P<0.01 or P<0.05). Additionally, the Xiangfu (Cyperi Rhizoma) volatile oil group showed decreased caspase-1 protein expression (P<0.05), while the fluoxetine group showed a decreasing trend in caspase-1 protein expression without statistical significance (P>0.05). Conclusion Xiangfu (Cyperi Rhizoma) volatile oil may exert antidepressant effects on PPD by inhibiting hippocampal neuroinflammation mediated by the TLR4/NF-κB/NLRP3 signaling pathway, providing experimental evidence for its potential as an intervention drug for PPD. |
| Key words: postpartum depression Xiangfu (Cyperi Rhizoma) volatile oil TLR4/NF-κB/NLRP3 signaling pathway inflammatory factor |
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