A new pharmacological effect of levornidazole: Inhibition of NLRP3 inflammasome activation
A new pharmacological effect of levornidazole: Inhibition of NLRP3 inflammasome activation
复制标题
左奥硝唑的新药理作用：抑制NLRP3炎症小体激活
DOI：
10.1016/j.bcp.2015.06.030
复制
发表时间：
2015
影响因子：
5.8
通讯作者：
Xu Qiang
中科院分区：
文献类型：
--
作者：
Wang Xingqi;Wang Shiyu;Hu Chunhui;Chen Wei;Shen Yan;Wu Xuefeng;Sun Yang;Xu Qiang
最初用于抑制厌氧菌和原生动物感染的左奥硝唑，目前已知具有新的药理作用。在这项研究中，我们研究了左奥硝唑对NOD样受体蛋白3（NLRP 3）炎性小体介导的巨噬细胞释放IL-1β和IL-18的可能调节作用。PMA预处理的THP-1巨噬细胞中NLRP 3炎性体可被脂多糖（LPS）和ATP或三磷酸腺苷（MSU）激活。令人惊讶的是，一项体外研究表明，左奥硝唑通过阻断NLRP 3炎性体的活化来抑制IL-1β和IL-18的分泌。然而，右旋硝唑几乎不能抑制NLRP 3炎性小体。左奥硝唑对临床厌氧菌的活性与右奥硝唑相似，药代动力学性质相同。此外，这两种化合物都不能改善T细胞介导的炎症。因此，我们使用广泛应用的葡聚糖硫酸钠（DSS）诱导的结肠炎和LPS诱导的内毒素休克的NLRP 3炎性小体相关模型，以证实左旋咪唑在体内的新药理作用。体内研究证实了左奥硝唑的新活性，因为在所测试的体内模型中，左奥硝唑对NLRP 3炎性小体的抑制作用比右奥硝唑的改善效果更好。此外，发现左奥硝唑的这种抑制作用至少部分是通过减少线粒体ROS产生而不抑制NF-κB活化来实现的。总之，这些数据描述了左奥硝唑作为NLRP 3炎性体活化抑制剂的新药理学作用。
Levornidazole, which was originally used to inhibit anaerobic and protozoal infections, is currently known to possess a novel pharmacological effect. In this study, we investigated the possible modulation by levornidazole of NOD-like receptor protein 3 (NLRP3) inflammasome-mediated IL-1β and IL-18 release from macrophages. The NLRP3 inflammasome could be activated by lipopolysaccharide (LPS) plus ATP or monosodium urate (MSU) in PMA-pretreated THP-1 macrophages. Surprisingly, anin vitrostudy showed that levornidazole suppressed IL-1β and IL-18 secretion by blocking the activation of the NLRP3 inflammasome. However, dextrornidazole barely suppressed the NLRP3 inflammasome. Levornidazole displays activity similar to that of dextrornidazole against clinical anaerobic bacteria, and they possess the same pharmacokinetic properties. Moreover, both of these compounds were unable to ameliorate T cell-mediated inflammation. Therefore, we used the widely applied NLRP3 inflammasome-related models of dextran sodium sulfate (DSS)-induced colitis and LPS-induced endotoxin shock to confirm the novel pharmacological effect of levornidazolein vivo. Thein vivostudies verified the novel activity of levornidazole because the inhibition of NLRP3 inflammasome by levornidazole contributed to a better ameliorating effect than that of dextrornidazole in thein vivomodels tested. Furthermore, this inhibitory effect of levornidazole was found to be at least partially achieved by decreasing the mitochondrial ROS generation without inhibiting NF-κB activation. In summary, these data describe a new pharmacological effect of levornidazole as an inhibitor of NLRP3 inflammasome activation.