Ciclopirox inhibits NLRP3 inflammasome activation via protecting mitochondria and ameliorates imiquimod-induced psoriatic inflammation in mice

  • Eur J Pharmacol. 2022 Sep 5;930:175156. doi: 10.1016/j.ejphar.2022.175156.
Shuli Liang  1 ,  Zhongjin Yang  1 ,  Lei Hua  1 ,  Yanhong Chen  1 ,  Yinghua Zhou  1 ,  Yitao Ou  1 ,  Xiuhui Chen  1 ,  Hu Yue  1 ,  Xiangyu Yang  1 ,  Xinyi Wu  1 ,  Wenhui Hu  2 ,  Ping Sun  3
Affiliations
  • 1. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
  • 2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address: [email protected].
  • 3. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address: [email protected].
PMID: 35868446 DOI: 10.1016/j.ejphar.2022.175156
Abstract

The maturation and secretion of interleukin-1β (IL-1β) mediated by NLRP3 inflammasome activation plays an important role in the progression of many inflammatory diseases. Inhibition of NLRP3 inflammasome activation may be a promising strategy to treat these inflammation-driven diseases, such as psoriasis. As a broad-spectrum Antifungal agent, ciclopirox (CPX) is widely used in the treatment of dermatomycosis. Although CPX has been reported to have anti-inflammatory effects in many studies, there has been little research into its underlying mechanisms. In our study, CPX reduced lipopolysaccharide (LPS)/nigericin-induced NLRP3 inflammasome activation (IC50: 1.684 μM). Mechanistically, CPX upregulated peroxisome proliferator-activated receptor-γ coactivator-1α expression (by 82.7% at 5 μM and 87.5% at 10 μM) to protect mitochondria. Our studies showed that CPX reduced mitochondrial Reactive Oxygen Species production, increased mitochondrial membrane potential, elevated mitochondrial biosynthesis, and up-regulated intracellular adenosine triphosphate level. Furthermore, treatment with CPX promoted the up-regulation of mRNA expression, which involved mitochondrial biosynthesis (NRF1, NRF2, TFAM) and antioxidation (SOD1 and CAT). In addition, CPX ameliorated inflammatory response in imiquimod-induced psoriasis mice. This study provides a potential pharmacological mechanism for CPX to treat psoriasis and Other NLRP3-driven inflammatory diseases.

Keywords
Ciclopirox; IL-1β; Macrophage; Mitochondrial reactive oxygen species; NLRP3 inflammasome; Psoriasis.
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