Mechanisms of Antidepressant Effect of Zhizi Houpotang and Its Herbal Pairs Based on NLRP3/GSDMD Signaling Pathway
10.13422/j.cnki.syfjx.20252203
- VernacularTitle: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
- Author:
Chang CHEN
1
;
Ziwen GUO
2
;
Tingyu SONG
1
;
Yan WANG
3
;
Baomei XIA
4
;
Weiwei TAO
3
Author Information
1. School of Elderly Care Services and Management， Nanjing University of Chinese Medicine， Nanjing 210023， China
2. Drum Tower Clinical Medical College， Nanjing University of Chinese Medicine， Nanjing 210009， China
3. School of Integrative Medicine， Nanjing University of Chinese Medicine， Nanjing 210023， China
4. Faculty of Rehabilitation Science， Nanjing Normal University of Special Education， Nanjing 210038， China
- Publication Type:Journal Article
- Keywords:
depression;
Zhizi Houpotang;
herbal pair;
NOD-like receptor protein 3 （NLRP3） inflammasome;
gasdermin D （GSDMD）
- From:
Chinese Journal of Experimental Traditional Medical Formulae
2026;32(6):72-80
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTaking 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. MethodsC57BL/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-1β （IL-1β） 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）， and the presynaptic protein Synapsin 1 in PFC tissues. Golgi staining was used to assess dendritic spine density of neurons in the PFC. ResultsCompared 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 （P<0.01）， the levels of IL-1β and IL-18 in serum and the PFC were significantly elevated （P<0.01）， and the protein expression levels of Panx1， P2RX7， NLRP3， ASC， Caspase-1， and GSDMD in the PFC were significantly upregulated （P<0.01）. In contrast， the protein expression levels of PSD95 and Synapsin 1 were significantly downregulated （P<0.01）， and neuronal dendritic spine density was significantly reduced （P<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 （P<0.01）. The GF-AFI herbal pair group improved all the above indicators except P2RX7， Caspase-1， GSDMD， and PSD95 （P<0.05， P<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. ConclusionZhizi 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-1β 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.
