Antidepressant mechanism of sns in repairing synaptic damage via the GPR120/NLRP3 pathway-mediated inhibition of microglial M1 polarization.

BACKGROUND

Suppressing the M1 polarization of microglia, thereby improving synaptic plasticity, is a key therapeutic strategy for depression. GPR120 is a critical regulator of cellular inflammatory responses, exerting its function by negative modulation of NLRP3 signaling pathway. Sinisan (SNS), a classic traditional Chinese medicine formula, demonstrates potential in addressing inflammation and psychiatric conditions, yet its exact mechanisms remain to be fully clarified.

PURPOSE: This study aims to explore how SNS regulates microglial polarization following stress-induced injury and clarify the potential molecular mechanisms underlying antidepressant actions.

METHODS

The depression model was established using LPS+CUMS. After administration of SNS, behavioral tests were conducted to evaluate changes in depressive-like behaviors. Synaptic ultrastructural changes in the prefrontal cortex (PFC) were examined by transmission electron microscopy. Synaptic plasticity, microglial polarization, NLRP3 inflammasome activation, and GPR120 internalization in the PFC were assessed. Protein-protein interactions were analyzed by co-immunoprecipitation. The material basis of SNS in regulating GPR120 was explored through molecular docking, liquid chromatography-mass spectrometry, cellular thermal shift assay.

RESULTS

SNS effectively alleviated depressive-like behaviors and synaptic damage, while inhibiting microglial polarization toward the M1 phenotype, suppressing NLRP3 inflammasome self-assembly and activation, and promoting GPR120 internalization. Stigmasterol was identified as the active component of SNS responsible for its antidepressant effects.

CONCLUSION

SNS promotes the internalization of GPR120 receptors and inhibits NLRP3 inflammasome self-assembly, thereby reducing microglial M1 polarization in the PFC. This mechanism restores synaptic plasticity and exerts antidepressant effects.