Ulinastatin attenuates Lipopolysaccharide-induced Microglia Activation and cognitive deficits via a MAPKs/JAK-STATs Dependent Manner
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Neurodegenerative diseases are one kind of age-associated diseases with specific pathological features. Microglia are fundamental for the development and function of brain. Modulation of this microglial activation in neurodegenerative disease may offer novel therapeutic strategies. Ulinastatin (UTI) is an intrinsic serine-protease urinary trypsin inhibitor that are widely used to treat patients with acute inflammatory disorders. Although the anti-inflammatory activities of UTI have been investigated, the mechanisms underlying their effects on microglial activation remain largely unknown. In the present study, we investigated the effects of UTI on lipopolysaccharide (LPS)-induced microglial activation in both rats and BV2 mouse microglial cells, focusing on the involvement of MAPK and JAK-STAT signaling pathways. To accomplish this, we performed Morris water maze, enzyme-linked immunosorbent assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunohistochemical and immunoflourescence, western blot analysis. The results demonstrated that LPS-induced microglia activation via MAPK and JAK-STATs signaling pathways, leading to the upregulation of TNF-α and IL-1β from activated microglia, which ultimately resulted in spatial learning and memory deficits in rats. UTI suppressed LPS-induced microglia activation by modulating MAPK and JAK-STAT signaling pathways, concurrently downregulating TNF-α and IL-1β levels in both rats and BV2 mouse microglial cells, thereby attenuating LPS-induced spatial memory impairment. These findings demonstrate that ulinastatin exerts anti-inflammatory effects and suppresses microglia activation through downregulation of TNF-α and IL-1β, prevents spatial memory impairment induced by LPS. UTI demonstrates an inhibitory effect on TNF-α and IL-1β release in activated microglial cells and may represent an effective therapeutic agent for controlling neurological disorders.
