Mechanisms of Antidepressant Effect of Zhizi Houpotang and Its Herbal Pairs Based on NLRP3/GSDMD Signaling Pathway

CHEN Chang; GUO Ziwen; SONG Tingyu; WANG Yan; XIA Baomei; TAO Weiwei

doi:10.13422/j.cnki.syfjx.20252203

您当前的位置：

首页 >

文章列表页 >

Mechanisms of Antidepressant Effect of Zhizi Houpotang and Its Herbal Pairs Based on NLRP3/GSDMD Signaling Pathway

更新时间：2026-02-28

- Mechanisms of Antidepressant Effect of Zhizi Houpotang and Its Herbal Pairs Based on NLRP3/GSDMD Signaling Pathway
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 32, Issue 6, Pages: 72-80(2026)
- 作者机构：
  
  1.南京中医药大学养老服务与管理学院，南京 210023
  2.南京中医药大学鼓楼临床医学院，南京 210009
  3.南京中医药大学中西医结合学院，南京 210023
  4.南京特殊教育师范学院康复科学学院，南京 210038
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20252203
  CLC： R289;R259;R285
- Received：08 July 2025，
  
  Revised：2025-09-18，
  
  Accepted：15 October 2025，
  
  Online First：17 October 2025，
  
  Published：20 March 2026
- 稿件说明：
移动端阅览
陈畅,郭紫文,宋婷宇等.基于NLRP3/GSDMD信号通路探究栀子厚朴汤及其药对的抗抑郁作用[J].中国实验方剂学杂志,2026,32(06):72-80.

CHEN Chang,GUO Ziwen,SONG Tingyu,et al.Mechanisms of Antidepressant Effect of Zhizi Houpotang and Its Herbal Pairs Based on NLRP3/GSDMD Signaling Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2026,32(06):72-80.
陈畅,郭紫文,宋婷宇等.基于NLRP3/GSDMD信号通路探究栀子厚朴汤及其药对的抗抑郁作用[J].中国实验方剂学杂志,2026,32(06):72-80. DOI： 10.13422/j.cnki.syfjx.20252203.

CHEN Chang,GUO Ziwen,SONG Tingyu,et al.Mechanisms of Antidepressant Effect of Zhizi Houpotang and Its Herbal Pairs Based on NLRP3/GSDMD Signaling Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2026,32(06):72-80. DOI： 10.13422/j.cnki.syfjx.20252203.

摘要

目的

以经典药对配伍研究为切入点，深入探讨中药复方栀子厚朴汤抗抑郁作用的物质基础与配伍规律，并重点阐明其通过调控NOD样受体蛋白3（NLRP3）/消皮素D（GSDMD）信号通路介导的神经炎症反应，改善神经元突触可塑性发挥抗抑郁作用的效应机制。

方法

将C57BL/6J小鼠随机分为空白组、慢性不可预知温和应激（CUMS）抑郁模型组、栀子厚朴汤全方组（6 g·kg

-1

·d

-1

）、厚朴-枳实药对组（4.2 g·kg

-1

·d

-1

）、栀子-厚朴药对组（4.2 g·kg

-1

·d

-1

）、栀子-枳实药对组（3.6 g·kg

-1

·d

-1

）及阳性药组（氟西汀，12 mg·kg

-1

·d

-1

），通过行为学检测评估小鼠抑郁样行为；采用免疫荧光染色标记并定量小鼠前额叶皮层（PFC）组织中小胶质细胞标志物离子钙结合适配器分子1（Iba1）及嘌呤能受体P2X配体门控离子通道7（P2RX7）的表达；应用酶联免疫吸附测定法（ELISA）检测血清和PFC组织中炎症因子白细胞介素（IL-1

）、白细胞介素18（IL-18）水平；蛋白免疫印迹法（Western blot）检测PFC组织中泛连接蛋白1（Panx1）、P2RX7、NLRP3、凋亡相关斑点样蛋白（ASC）、胱天蛋白酶-1（Caspase-1）、GSDMD、突触后致密蛋白95（PSD95）及突触前蛋白突触素1（Synapsin1）的表达；通过高尔基染色评估PFC神经元树突棘密度。

结果

与空白组比较，抑郁模型组小鼠表现出显著的抑郁样行为，并且PFC组织中Ibal及P2RX7免疫荧光面积显著增加（

0.01），血清及PFC中IL-1

、IL-18水平显著升高（

0.01），PFC组织中Panx1、P2RX7、NLRP3、ASC、Caspase-1、GSDMD蛋白表达显著上调（

0.01），而PSD95和Synapsin1蛋白表达显著下调（

0.01），同时神经元树突棘密度显著降低（

0.01）。与模型组比较，栀子厚朴汤全方组、栀子-厚朴药对组上述各指标均明显改善（

0.01），栀子-枳实药对组可改善除P2RX7、Caspase-1、GSDMD、PSD95之外的其他上述指标（

0.05，

0.01）。而厚朴-枳实药对组与模型组相比，对上述各指标的改善均无统计学意义。

结论

栀子厚朴汤及其关键药对，即栀子-厚朴，能有效改善CUMS诱导的小鼠抑郁样行为。其核心抗抑郁机制可能在于通过抑制P2RX7/Panx1信号，阻断NLRP3/GSDMD介导的焦亡通路，从而显著降低炎症因子IL-1

、IL-18的释放；同时上调突触相关蛋白PSD95和Synapsin1的表达并增加树突棘密度，促进突触可塑性的恢复。研究

结果提示，栀子在该复方抗抑郁效应中扮演关键角色，且栀子与厚朴的配伍可能是发挥核心治疗作用的主要药对组合。

Abstract

Objective

Taking classical herbal pair compatibility research as the entry point， this study aimed to deeply investigate the material basis and compatibility rules underlying the antidepressant effects of the traditional Chinese medicine （TCM） formula Zhizi Houpotang， and to elucidate its antidepressant mechanism， with a particular focus on its regulation of neuroinflammatory responses mediated by the NOD-like receptor protein 3 （NLRP3）/gasdermin D （GSDMD） signaling pathway and the consequent improvement of neuronal synaptic plasticity.

Methods

C57BL/6J mice were randomly divided into a blank control group， a chronic unpredictable mild stress （CUMS） depression model group， a Zhizi Houpotang full-formula group （6 g·kg

-1

·d

-1

）， a Magnoliae Officinalis Cortex （MOC）-Aurantii Fructus Immaturus （AFI） herbal pair group （4.2 g·kg

-1

·d

-1

）， a Gardeniae Fructus （GF）-MOC herbal pair group （4.2 g·kg

-1

·d

-1

）， a GF-AFI herbal pair group （3.6 g·kg

-1

·d

-1

）， and a positive drug group （fluoxetine， 12 mg·kg

-1

·d

-1

）. Depressive-like behaviors in mice were evaluated using behavioral tests. Immunofluorescence staining was used to label and quantify the expression of the microglial marker ionized calcium-binding adaptor molecule 1 （Ibal） and the purinergic receptor P2X ligand-gated ion channel 7 （P2RX7） in the prefrontal cortex （PFC）. Enzyme-linked immunosorbent assay （ELISA） was applied to detect the levels of inflammatory cytokines interleukin-1

（IL-1

） and interleukin-18 （IL-18） in serum and PFC tissues. Western blot was employed to determine the expression of pannexin 1 （Panx1）， P2RX7， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， Caspase-1， GSDMD， postsynaptic density protein 95 （PSD95）， a

nd the presynaptic protein Synapsin 1 in PFC tissues. Golgi staining was used to assess dendritic spine density of neurons in the PFC.

Results

Compared with the blank control group， the depression model group exhibited significant depressive-like behaviors. In addition， the immunofluorescence areas of Ibal and P2RX7 in the PFC were significantly increased （

0.01）， the levels of IL-1

and IL-18 in serum and the PFC were significantly elevated （

0.01）， and the protein expression levels of Panx1， P2RX7， NLRP3， ASC， Caspase-1， and GSDMD in the PFC were significantly upregulated （

0.01）. In contrast， the protein expression levels of PSD95 and Synapsin 1 were significantly downregulated （

0.01）， and neuronal dendritic spine density was significantly reduced （

0.01）. Compared with the model group， the Zhizi Houpotang full-formula group and the GF-MOC herbal pair group showed significant improvement in all the above indicators （

0.01）. The GF-AFI herbal pair group improved all the above indicators except P2RX7， Caspase-1， GSDMD， and PSD95 （

0.05，

0.01）. In contrast， the MOC-AFI herbal pair group showed no statistically significant improvement in any of the above indicators compared with the model group.

Conclusion

Zhizi Houpotang and its key herbal pair， GF-MOC， can effectively ameliorate CUMS-induced depressive-like behaviors in mice. Its core antidepressant mechanism may involve inhibition of P2RX7/Panx1 signaling， thereby blocking the NLRP3/GSDMD-mediated pyroptosis pathway and significantly reducing the release of inflammatory cytokines IL-1

and IL-18. Simultaneously， it upregulates the expression of synapse-related proteins PSD95 and Synapsin 1 and increases dendritic spine density， promoting the recovery of synaptic plasticity. These results suggest that

GF plays a key role in the antidepressant effects of this formula， and that the compatibility of GF with MOC may represent the principal herbal pair combination responsible for its core therapeutic action.

关键词

Keywords

references

李凌江 . 中国抑郁障碍防治指南［M］. 北京：中华医学电子音像出版社， 2015 .

LI L J . Chinese Guidelines for Prevention and Treatment of Depression ［M］. Beijing ： Chinese Medical Electronic and Audio-Visual Publishing House ， 2015 .

TOMAZ V S ， CHAVES FILHO A J M ， CORDEIRO R C ， et al . Antidepressants of different classes cause distinct behavioral and brain pro- and anti-inflammatory changes in mice submitted to an inflammatory model of depression ［J］. J Affect Disord ， 2020 ， 268 ： 188 - 200 .

郭冬静，潘文超，王思嘉，等 . 神经免疫炎症交互作用在中医药治疗抑郁症中的研究进展［J］. 中国比较医学杂志， 2024 ， 34 （ 8 ）： 167 - 177

GUO D J ， PAN W C ， WANG S J ， et al . Research development on the interaction between neuroimmunity and inflammation in the treatment of depressive disorder by traditional Chinese medicine ［J］. Chin J Comp Med ， 2024 ， 34 （ 8 ）： 167 - 177 .

WU A ， ZHANG J . Neuroinflammation，memory，and depression：New approaches to hippocampal neurogenesis ［J］. J Neuroinflammation ， 2023 ， 20 （ 1 ）： 283 .

CAI L ， MU Y R ， LIU M M ， et al . Antidepressant-like effects of penta-acetyl geniposide in chronic unpredictable mild stress-induced depression rat model：Involvement of inhibiting neuroinflammation in prefrontal cortex and regulating hypothalamic-pituitary-adrenal axis ［J］. Int Immunopharmacol ， 2020 ， 80 ： 106182 .

YE Z ， WANG J ， FANG F ， et al . Zhi-Zi-Hou-Po decoction alleviates depressive-like behavior and promotes hippocampal neurogenesis in chronic unpredictable mild stress induced mice via activating the BDNF/TrkB/CREB pathway ［J］. J Ethnopharmacol ， 2024 ， 319 （ Pt 3 ）： 117355 .

AKCAY E ， KARATAS H . P2X7 receptors from the perspective of NLRP3 inflammasome pathway in depression：Potential role of cannabidiol ［J］. Brain Behav Immun Health ， 2024 ， 41 ： 100853 .

WANG D ， WANG H ， GAO H ， et al . P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes ［J］. Cell Biosci ， 2020 ， 10 ： 28 .

CHEN S P ， QIN T ， SEIDEL J L ， et al . Inhibition of the P2X7-PANX1 complex suppresses spreading depolarization and neuroinflammation ［J］. Brain ， 2017 ， 140 （ 6 ）： 1643 - 1656 .

HAN Q ， LI W ， CHEN P ， et al . Microglial NLRP3 inflammasome-mediated neuroinflammation and therapeutic strategies in depression ［J］. Neural Regen Res ， 2024 ， 19 （ 9 ）： 1890 - 1898 .

RIBEIRO D E ， MÜLLER H K ， ELFVING B ， et al . Antidepressant-like effect induced by P2X7 receptor blockade in FSL rats is associated with BDNF signalling activation ［J］. J Psychopharmacol ， 2019 ， 33 （ 11 ）： 1436 - 1446 .

朱鹤云，王开鼎，史健艺，等 . UFLC-MS/MS法同时测定栀子厚朴汤中10个成分的含量［J］. 药物分析杂志， 2020 ， 40 （ 10 ）： 1751 - 1759 .

ZHU H Y ， WANG K D ， SHI J Y ， et al . Simultaneous determination of ten components in Zhizi Houpo decoction by UFLC-MS/MS ［J］. Chin J Pharm Anal ， 2020 ， 40 （ 10 ）： 1751 - 1759 .

徐叔云，卞如濂，陈修，等 . 药理实验方法学［M］. 3版 . 北京：人民卫生出版社， 2002 ： 1261 - 1266 .

XU S Y ， BIAN R L ， CHEN X ， et al . Pharmacological Experimental Methodology （Third Edition）［M］. 3rd. Beijing ： People's Medical Publishing House ， 2002 ： 1261 - 1266 .

NAIR A B ， JACOB S . A simple practice guide for dose conversion between animals and human ［J］. J Basic Clin Pharm ， 2016 ， 7 （ 2 ）： 27 - 31 .

WANG J ， XIN J ， XU X ， et al . Bacopaside Ⅰ alleviates depressive-like behaviors by modulating the gut microbiome and host metabolism in CUMS-induced mice ［J］. Biomed Pharmacother ， 2024 ， 170 ： 115679 .

初云海，贾静丽，田明，等 . 栀子厚朴汤的药效活性成分研究进展［J］. 中医药信息， 2017 ， 34 （ 6 ）： 127 - 129 .

CHU Y H ， JIA J L ， TIAN M ， et al . Research progress on the active components of Zhizi Houpo decoction ［J］. Chin J Inf Tradit Chin Med ， 2017 ， 34 （ 6 ）： 127 - 129 .

LIU M Y ， YIN C Y ， ZHU L J ， et al . Sucrose preference test for measurement of stress-induced anhedonia in mice ［J］. Nat Protoc ， 2018 ， 13 （ 7 ）： 1686 - 1698 .

CRYAN J F ， MOMBEREAU C ， VASSOUT A . The tail suspension test as a model for assessing antidepressant activity：Review of pharmacological and genetic studies in mice ［J］. Neurosci Biobehav Rev ， 2005 ， 29 （ 4/5 ）： 571 - 625 .

ZIMCIKOVA E ， SIMKO J ， KARESOVA I ， et al . Behavioral effects of antiepileptic drugs in rats：Are the effects on mood and behavior detectable in open-field test？［J］. Seizure ， 2017 ， 52 ： 35 - 40 .

常丽萍，魏聪，贾振华 . 黄煌教授运用仲景经方治疗抑郁症经验［J］. 南京中医药大学学报， 2024 ， 40 （ 7 ）： 747 - 751 .

CHANG L P ， WEI C ， JIA Z H . Professor Huang's experience in treating depression with Zhongjing classic recipe ［J］. J Nanjing Univ Tradit Chin Med ， 2024 ， 40 （ 7 ）： 747 - 751 .

YU X W ， ZHU J ， GONG M ， et al . Effect of depression and the antidepressant fluoxetine on osseointegration：A pre-clinical in vivo experimental study ［J］. Clin Oral Implants Res ， 2024 ， 35 （ 10 ）： 1355 - 1366 .

XIA C Y ， GUO Y X ， LIAN W W ， et al . The NLRP3 inflammasome in depression：Potential mechanisms and therapies ［J］. Pharmacol Res ， 2023 ， 187 ： 106625 .

LI T ， LI Y ， CHEN J ， et al . Hyperibone J exerts antidepressant effects by targeting ADK to inhibit microglial P2X7R/TLR4-mediated neuroinflammation ［J］. J Adv Res ， 2025 ， 72 ： 571 - 589 .

LEAL G ， AFONSO P M ， SALAZAR I L ， et al . Regulation of hippocampal synaptic plasticity by BDNF ［J］. Brain Res ， 2015 ， 1621 ： 82 - 101 .

DUMAN R S ， AGHAJANIAN G K . Synaptic dysfunction in depression：Potential therapeutic targets ［J］. Science ， 2012 ， 338 （ 6103 ）： 68 - 72 .

PAŁUCHA-PONIEWIERA A ， BOBULA B ， RAFAŁO-ULIŃSKA A . The antidepressant-like activity and cognitive enhancing effects of the combined administration of （R）-ketamine and LY341495 in the CUMS model of depression in mice are related to the modulation of excitatory synaptic transmission and LTP in the PFC ［J］. Pharmaceuticals （Basel）， 2023 ， 16 （ 2 ）： 288 .

LI P ， HUANG W ， CHEN Y ， et al . Acupuncture alleviates CUMS-induced depression-like behaviors by restoring prefrontal cortex neuroplasticity ［J］. Neural Plast ， 2023 ， doi： 10.1155/2023/1474841 http://dx.doi.org/10.1155/2023/1474841 .

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Gardeniae Fructus and Its Prescriptions in Treatment of Depression： A Review

Effect of Albiziae Flos and Polygalae Radix Alone and Their Combination on Depression-like Behavior and CREB and NOX2 Expression in Hippocampus of Chronic Unpredictable Stress-induced Rats

Mechanism of Xiaozheng Zhitong Paste in Alleviating Bone Cancer Pain by Regulating Microglial Pyroptosis Based on PINK1/Parkin/NLRP3 Signaling Pathway

Mechanism of Traditional Chinese Medicine in Comorbidity of Parkinson's Disease and Depression： A Review

Related Author

TIAN Lei

LI Yucheng

BAI Ming

WANG Baoying

XU Erping

Bing-mei WANG

Pan QIAO

Wei WANG

Related Institution

Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae，Academy of Chinese Medical Sciences，Henan University of Chinese Medicine

Changchun University of Chinese Medicine

Jilin Agricultural Science and Technology University

Changchun Yingshi Medicine Clinics

The First Clinical College， Liaoning University of Traditional Chinese Medicine（TCM）

AI问答

Postal code：100700
Tel：010-84076882 Email：syfjx_2010@188.com
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备11006657号-10 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰