Scholarlink

<p>Modified Xiaoyao San (MXYS) is a well-established clinical prescription for the treatment of depression in China. While MXYS shows considerable promise for the development of new antidepressants, its pharmacological mechanisms remain poorly understood. This study aims to investigate the antidepressant potential and underlying mechanisms of MXYS in lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Behavioral assessments (sucrose preference test, tail suspension test, open field test) demonstrated that MXYS significantly ameliorated LPS-induced anhedonia and behavioral despair. Histopathological and molecular analyses revealed that MXYS mitigated LPS-induced neuronal damage in the prefrontal cortex (PFC), restored dendritic spine density, and rebalanced neuroinflammatory cytokines by reducing the pro-inflammatory IL-1β and elevating the anti-inflammatory IL-10. Moreover, MXYS promoted microglial polarization toward the anti-inflammatory M2 phenotype (CD206⁺) while suppressing the pro-inflammatory M1 phenotype (CD68⁺). Mechanistically, MXYS inhibited NLRP3 inflammasome activation and pyroptosis through the upregulation of the E3 ubiquitin ligase TRIM31, which facilitated NLRP3 degradation. Transmission electron microscopy confirmed that MXYS inhibited LPS-induced microglial pyroptosis, as evidenced by reduced Gasdermin D (GSDMD) expression and preserved cellular ultrastructure. In vitro validation using LPS-stimulated BV2 microglia further corroborated the MXYS-mediated suppression of NLRP3 inflammasome activity, pyroptosis, and inflammatory cytokine dysregulation, alongside enhanced TRIM31 expression. Collectively, these findings demonstrate that MXYS exerts antidepressant effects by modulating neuroinflammation through TRIM31-dependent NLRP3 ubiquitination, microglial phenotype switching, and the inhibition of pyroptosis, providing novel insights into its therapeutic potential for the treatment of depression.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Modified Xiaoyao San ameliorates LPS-induced depression-like behavior by inhibiting NLRP3-mediated microglial pyroptosis

  • 期刊论文

  • 发表日期：

    2025年11月22日

查看全文
  • Lei Tian,
  • Pan Su,
  • Gang Feng,
  • Shuaijun Peng,
  • Liming Liu,
  • Xiangli Yan,
  • Xianghua Liu,
  • Yucheng Li,
  • Ming Bai,
  • Baoying Wang,
  • Erping Xu

摘要

Modified Xiaoyao San (MXYS) is a well-established clinical prescription for the treatment of depression in China. While MXYS shows considerable promise for the development of new antidepressants, its pharmacological mechanisms remain poorly understood. This study aims to investigate the antidepressant potential and underlying mechanisms of MXYS in lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Behavioral assessments (sucrose preference test, tail suspension test, open field test) demonstrated that MXYS significantly ameliorated LPS-induced anhedonia and behavioral despair. Histopathological and molecular analyses revealed that MXYS mitigated LPS-induced neuronal damage in the prefrontal cortex (PFC), restored dendritic spine density, and rebalanced neuroinflammatory cytokines by reducing the pro-inflammatory IL-1β and elevating the anti-inflammatory IL-10. Moreover, MXYS promoted microglial polarization toward the anti-inflammatory M2 phenotype (CD206⁺) while suppressing the pro-inflammatory M1 phenotype (CD68⁺). Mechanistically, MXYS inhibited NLRP3 inflammasome activation and pyroptosis through the upregulation of the E3 ubiquitin ligase TRIM31, which facilitated NLRP3 degradation. Transmission electron microscopy confirmed that MXYS inhibited LPS-induced microglial pyroptosis, as evidenced by reduced Gasdermin D (GSDMD) expression and preserved cellular ultrastructure. In vitro validation using LPS-stimulated BV2 microglia further corroborated the MXYS-mediated suppression of NLRP3 inflammasome activity, pyroptosis, and inflammatory cytokine dysregulation, alongside enhanced TRIM31 expression. Collectively, these findings demonstrate that MXYS exerts antidepressant effects by modulating neuroinflammation through TRIM31-dependent NLRP3 ubiquitination, microglial phenotype switching, and the inhibition of pyroptosis, providing novel insights into its therapeutic potential for the treatment of depression.

Graphical Abstract