INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats.
INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats.
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DOI：
10.1016/j.bbi.2020.09.016
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Hu X;Yan J;Huang L;Araujo C;Peng J;Gao L;Liu S;Tang J;Zuo G;Zhang JH
炎症小体介导的神经炎症在蛛网膜下腔出血（SAH）后早期脑损伤（EBI）的发病机制中起重要作用。TGR5受体的激活已被证明在多种神经系统疾病中具有神经保护作用。本研究旨在探讨特异性合成TGR5激动剂INT-777在SAH后减轻NLRP3-ASC炎性体激活和减轻神经炎症的作用。实验使用了184只雄性斯普拉格·道利大鼠。SAH由血管内穿孔引起。在SAH诱导后1小时经鼻给药INT-777。为了阐明在EBI过程中nt -777对炎性体激活的影响所涉及的信号通路，我们在SAH前48小时和1小时分别给药TGR5敲除CRISPR和PKA抑制剂H89。进行SAH分级、短期和长期神经行为评估、脑含水量、免疫印迹、免疫荧光染色和尼氏染色。内源性TGR5、p-PKA、NLRP3-ASC炎性体在SAH后表达升高。给药nt -777显著降低小胶质细胞NLRP3-ASC炎性体的激活，减少脑水肿和神经炎症，导致SAH后24小时短期神经行为功能改善。在SAH后24小时，TGR5 CRISPR或PKA抑制剂（H89）可消除nt -777对NLRP3-ASC炎性体、促炎细胞因子（IL-6、IL-1β和TNF-a）和中性粒细胞浸润的抗炎作用。此外，早期给药INT-777可减轻SAH后28 d海马神经元变性。在SAH后EBI中，INT-777部分通过TGR5/cAMP/PKA信号通路减弱NLRP3-ASC炎性体依赖性神经炎症。早期给药INT-777可能作为SAH背景下EBI管理的潜在治疗策略。
Inflammasome-mediated neuroinflammation plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The activation of the TGR5 receptor has been shown to be neuroprotective in a variety of neurological diseases. This study aimed to investigate the effects of the specific synthetic TGR5 agonist, INT-777, in attenuating NLRP3-ASC inflammasome activation and reducing neuroinflammation after SAH. One hundred and eighty-four male Sprague Dawley rats were used. SAH was induced by the endovascular perforation. INT-777 was administered intranasally at 1 h after SAH induction. To elucidate the signaling pathway involved in the effect of INT-777 on inflammasome activation during EBI, TGR5 knockout CRISPR and PKA inhibitor H89 were administered intracerebroventricularly and intraperitoneally at 48 h and 1 h before SAH. The SAH grade, short- and long-term neurobehavioral assessments, brain water content, western blot, immunofluorescence staining, and Nissl staining were performed. The expressions of endogenous TGR5, p-PKA, and NLRP3-ASC inflammasome were increased after SAH. INT-777 administration significantly decreased NLRP3-ASC inflammasome activation in microglia, reduced brain edema and neuroinflammation, leading to improved short-term neurobehavioral functions at 24 h after SAH. The administration of TGR5 CRISPR or PKA inhibitor (H89) abolished the anti-inflammation effects of INT-777, on NLRP3-ASC inflammasome, pro-inflammatory cytokines (IL-6, IL-1β, and TNF-a), and neutrophil infiltration at 24 h after SAH. Moreover, early administration of INT-777 attenuated neuronal degeneration in hippocampus on 28 d after SAH. INT-777 attenuated NLRP3-ASC inflammasome-dependent neuroinflammation in the EBI after SAH, partially via TGR5/cAMP/PKA signaling pathway. Early administration of INT-777 may serve as a potential therapeutic strategy for EBI management in the setting of SAH.
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作者：
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影响因子：
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