State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Biochem Pharmacol. 2015 Sep 15;97(2):178-88. doi: 10.1016/j.bcp.2015.06.030. Epub 2015 Jul 23.
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, an in vitro study 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 levornidazole in vivo. The in vivo studies 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 the in vivo models 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.
左奥硝唑原本用于抑制厌氧和原生动物感染，目前已知具有新的药理学作用。在这项研究中，我们研究了左奥硝唑可能通过 NOD 样受体蛋白 3（NLRP3）炎性体调节巨噬细胞中白细胞介素 1β（IL-1β）和白细胞介素 18（IL-18）释放的作用。NLRP3 炎性体可被脂多糖（LPS）加三磷酸腺苷（ATP）或单钠尿酸盐（MSU）在 PMA 预处理的 THP-1 巨噬细胞中激活。令人惊讶的是，体外研究表明，左奥硝唑通过阻断 NLRP3 炎性体的激活来抑制 IL-1β和 IL-18 的分泌。然而，右旋奥硝唑几乎不能抑制 NLRP3 炎性体。左奥硝唑对临床厌氧菌的活性与右旋奥硝唑相似，它们具有相同的药代动力学特性。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 NLRP3 炎性体相关模型，即葡聚糖硫酸钠（DSS）诱导的结肠炎和 LPS 诱导的内毒素休克，来确认左奥硝唑在体内的新的药理学作用。体内研究验证了左奥硝唑的新活性，因为左奥硝唑抑制 NLRP3 炎性体有助于改善体内模型的效果，优于右旋奥硝唑。此外，这种左奥硝唑的抑制作用至少部分是通过减少线粒体 ROS 的产生而不是抑制 NF-κB 激活来实现的。总之，这些数据描述了左奥硝唑作为 NLRP3 炎性体激活抑制剂的新的药理学作用。
