INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats.
作者： Xiao Hu , Jun Yan , Lei Huang , Camila Araujo , Jun Peng
DOI: 10.1016/J.BBI.2020.09.016
关键词:
摘要: Abstract Background Inflammasome-mediated neuroinflammation plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The activation TGR5 receptor has been shown to be neuroprotective a variety neurological diseases. This study aimed investigate effects specific synthetic agonist, INT-777, attenuating NLRP3-ASC inflammasome and reducing after SAH. Methods One hundred eighty-four male Sprague Dawley rats were used. SAH was induced by endovascular perforation. INT-777 administered intranasally at 1 h induction. To elucidate signaling pathway involved effect on during EBI, knockout CRISPR PKA inhibitor H89 intracerebroventricularly intraperitoneally 48 before grade, short- long-term neurobehavioral assessments, water content, western blot, immunofluorescence staining, Nissl staining performed. Results expressions endogenous TGR5, p-PKA, increased administration significantly decreased microglia, reduced edema neuroinflammation, leading improved short-term functions 24 or (H89) abolished anti-inflammation inflammasome, pro-inflammatory cytokines (IL-6, IL-1β, TNF-a), neutrophil infiltration Moreover, attenuated neuronal degeneration hippocampus 28 d Conclusions inflammasome-dependent EBI SAH, partially via TGR5/cAMP/PKA pathway. Early may serve as potential therapeutic strategy for management setting
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