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Network Pharmacology and Validation of the Antidepressant Mechanisms of Qiangzhifang in a Chronic Restraint Stress-induced Depression Rat Model
Published on: June 6, 2025
Activation of microglial PPARγ by asperosaponin VI alleviates stress-induced depression and synaptic impairment
Yangyan Ge1, Chengyan Yang1, Meidan Wang2
1Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; Guizhou Key Laboratory for Germplasm Innovation and Resource-Efficient Utilization of Dao-di Herbs Guiyang 550025, China.
Background:
Depression is a common mental disorder affecting hundreds of millions worldwide. Targeting microglial peroxisome proliferator-activated receptor gamma (PPARγ) is regarded as one of the strategies to improve depression. However, a PPARγ activator capable of targeting brain microglia is currently lacking.
Objectives:
To screen novel natural PPARγ agonists targeting brain microglia from phytomedicine and analyze their antidepressant mechanisms.
Method:
Natural PPARγ agonists targeting brain microglia were identified from phytomedicine through molecular docking, kinetic simulations, surface plasmon resonance, and in vitro and in vivo approaches. The depression animal model was established using chronic unpredictable mild stress (CUMS). Depressive-like behaviors were evaluated using systematic behavioral analysis. Immunohistochemistry and Golgi staining were employed to evaluate the microglial phenotype and synaptic plasticity. The role of microglial PPARγ in improvement of neuroinflammation, synaptic impairment and depression was investigated in transgenic mice with conditional Pparg deletion in microglia.
Results:
A total of 18 potential compounds capable of activating microglial PPARγ were identified. Among them, asperosaponin VI (ASA-VI) showed stable binding affinity for multiple PPARγ subtypes and promoted PPARγ nuclear translocation in microglia. ASA-VI driven the phenotypic transformation of microglia toward a neuroprotective phenotype and inhibited neuroinflammation in vitro and in vivo. ASA-VI also improved hippocampal synaptic impairment and depressive-like behaviors in CUMS-exposed mice. Critically, conditional knockout of Pparg in microglia abolished the therapeutic effects of ASA-VI on neuroinflammation, synaptic impairment and depression.
Conclusion:
Our findings identify ASA-VI as a microglial PPARγ activator that remodels microglial phenotype, suppresses neuroinflammation and alleviates stress-induced depression and synaptic impairment.
