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.
Keywords: Dextrornidazole; IL-1β; Levornidazole; Macrophages; NLRP3 inflammasome.
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