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

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.