4.7 Article

A new pharmacological effect of levornidazole: Inhibition of NLRP3 inflammasome activation

Journal

BIOCHEMICAL PHARMACOLOGY
Volume 97, Issue 2, Pages 178-188

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2015.06.030

Keywords

Levomidazole; Dextromidazole; NLRP3 inflammasome; Macrophages; IL-1 beta

Funding

  1. National Natural Science Foundation of China [81422050, 91229109, 81373466, 81330079, 81273528]
  2. Natural Science Foundation of Jiangsu Province [BK2011053]

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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-1 beta 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-1 beta 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 levomidazole 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-kappa B activation. In summary, these data describe a new pharmacological effect of levornidazole as an inhibitor of NLRP3 inflammasome activation. (C) 2015 Elsevier Inc. All rights reserved.

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