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Abstract <p>Neurodegenerative diseases are age-associated disorders characterized by distinctive pathological features. Microglia are essential for brain development and function. Modulating microglial activation in neurodegenerative diseases may provide novel therapeutic strategies. Ulinastatin (UTI), an intrinsic serine protease inhibitor, is widely used to treat acute inflammatory disorders. Although the anti-inflammatory effects of UTI have been studied, the mechanisms by which it affects microglial activation remain incompletely understood. In this study, we investigated the effects of UTI on lipopolysaccharide (LPS)-induced microglial activation in both rats and BV2 mouse microglial cells, with a focus on the MAPK and JAK-STAT signaling pathways. We employed Morris water maze, ELISA, MTT assay, immunohistochemistry, immunofluorescence, and western blotting to evaluate the impact of UTI. Our results showed that LPS induced microglial activation via MAPK and JAK-STAT signaling, resulting in elevated TNF-α and IL-1β expression and spatial learning deficits in rats. UTI treatment suppressed LPS-induced microglial activation by modulating these pathways, reduced pro-inflammatory cytokine production, and attenuated spatial memory impairment. Notably, our findings provide new evidence that UTI exerts anti-inflammatory and neuroprotective effects by targeting MAPK/JAK-STAT-mediated microglial activation, suggesting its potential as a therapeutic agent for neuroinflammatory and neurodegenerative diseases.</p> Graphical Abstract <p>Graphical abstract illustrating the experimental design and key findings. In the in vivo study, rats received intraperitoneal injections of PBS or LPS, followed by UTI administration 3&#xa0;h later. One hour after UTI injection, cognitive function was assessed using the Morris water maze, and hippocampal tissues were subsequently collected for immunohistochemistry, ELISA, and western blot analysis. In the in vitro model, BV2 microglial cells were treated with LPS, followed by MTT assay, ELISA, and western blot experiments. The results demonstrate that UTI improves memory and cognitive function in rats, and suppresses the production of inflammatory cytokines by activated microglia, potentially via the MAPK and JAK-STAT signaling pathways.</p>

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Ulinastatin Attenuates Lipopolysaccharide-Induced Microglia Activation and Cognitive Deficits Via a MAPKs/JAK-STATs Dependent Manner

  • 期刊论文

  • 发表日期：

    2025年11月14日

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  • Yu Wang,
  • Zhongwei Fu,
  • Qi Fu,
  • Haiqin Xue,
  • Yang Zhou,
  • Xuefeng Shen,
  • Xiaoming Chen,
  • Jianbin Zhang,
  • Kejun Du

摘要

Abstract

Neurodegenerative diseases are age-associated disorders characterized by distinctive pathological features. Microglia are essential for brain development and function. Modulating microglial activation in neurodegenerative diseases may provide novel therapeutic strategies. Ulinastatin (UTI), an intrinsic serine protease inhibitor, is widely used to treat acute inflammatory disorders. Although the anti-inflammatory effects of UTI have been studied, the mechanisms by which it affects microglial activation remain incompletely understood. In this study, we investigated the effects of UTI on lipopolysaccharide (LPS)-induced microglial activation in both rats and BV2 mouse microglial cells, with a focus on the MAPK and JAK-STAT signaling pathways. We employed Morris water maze, ELISA, MTT assay, immunohistochemistry, immunofluorescence, and western blotting to evaluate the impact of UTI. Our results showed that LPS induced microglial activation via MAPK and JAK-STAT signaling, resulting in elevated TNF-α and IL-1β expression and spatial learning deficits in rats. UTI treatment suppressed LPS-induced microglial activation by modulating these pathways, reduced pro-inflammatory cytokine production, and attenuated spatial memory impairment. Notably, our findings provide new evidence that UTI exerts anti-inflammatory and neuroprotective effects by targeting MAPK/JAK-STAT-mediated microglial activation, suggesting its potential as a therapeutic agent for neuroinflammatory and neurodegenerative diseases.

Graphical Abstract

Graphical abstract illustrating the experimental design and key findings. In the in vivo study, rats received intraperitoneal injections of PBS or LPS, followed by UTI administration 3 h later. One hour after UTI injection, cognitive function was assessed using the Morris water maze, and hippocampal tissues were subsequently collected for immunohistochemistry, ELISA, and western blot analysis. In the in vitro model, BV2 microglial cells were treated with LPS, followed by MTT assay, ELISA, and western blot experiments. The results demonstrate that UTI improves memory and cognitive function in rats, and suppresses the production of inflammatory cytokines by activated microglia, potentially via the MAPK and JAK-STAT signaling pathways.