Palmatine Protects Against MSU-Induced Gouty Arthritis via Regulating the NF-κB/NLRP3 and Nrf2 Pathways

Drug Des Devel Ther. 2022 Jul 2:16:2119-2132. doi: 10.2147/DDDT.S356307. eCollection 2022.

Abstract

Purpose: Gouty arthritis could be triggered by the deposition of monosodium uric acid (MSU) crystals. Palmatine (PAL), a protoberberine alkaloid, has been proven to possess compelling health-beneficial activities. In this study, we aimed to explore the effect of PAL on LPS plus MSU crystal-stimulated gouty arthritis in vitro and in vivo.

Methods: PMA-differentiated THP-1 macrophages were primed with LPS and then stimulated with MSU crystal in the presence or absence of PAL. The expression of pro-inflammatory cytokines and oxidative stress-related biomarkers and signal pathway key targets were determined by ELISA kit, Western blot, immunohistochemistry and qRT-PCR, respectively. In addition, the anti-inflammatory and antioxidant activities of PAL on MSU-induced arthritis mice were also evaluated.

Results: The results indicated that PAL (20, 40 and 80 μM) dose-dependently decreased the mRNA expression and levels of pro-inflammatory cytokines (interleukin-1beta (IL-1β), IL-6, IL-18 and tumor necrosis factor alpha (TNF-α)). The levels of superoxide dismutase (SOD) and glutathione (GSH) were remarkably enhanced, while the level of malondialdehyde (MDA) was reduced. Western blot analysis revealed that PAL appreciably inhibited NF-κB/NLRP3 signaling pathways through inhibiting the phosphorylation of p-65 and IκBα, blocking the expression of NLRP3, ASC, IL-1β and Caspase-1, as well as enhancing the antioxidant protein expression of Nrf2 and HO-1. In vivo, PAL attenuated MSU-induced inflammation in gouty arthritis, as evidenced by mitigating the joint swelling, and decreasing the productions of IL-1β, IL-6, IL-18, TNF-α and MDA, while enhancing the levels of SOD and GSH. Moreover, PAL further attenuated the infiltration of neutrophils into joint synovitis.

Conclusion: PAL protected against MSU-induced inflammation and oxidative stress via regulating the NF-κB/NLRP3 and Nrf2 pathways. PAL may represent a potential candidate for the treatment of gouty arthritis.

Keywords: NF-κB/Nrf2 signal pathways; NLRP3 inflammasome; gouty arthritis; palmatine.

MeSH terms

  • Animals
  • Antioxidants / adverse effects
  • Arthritis, Gouty* / chemically induced
  • Arthritis, Gouty* / drug therapy
  • Arthritis, Gouty* / prevention & control
  • Berberine Alkaloids
  • Cytokines
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Interleukin-18
  • Interleukin-6
  • Lipopolysaccharides
  • Mice
  • NF-E2-Related Factor 2
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Superoxide Dismutase
  • Tumor Necrosis Factor-alpha / metabolism
  • Uric Acid

Substances

  • Antioxidants
  • Berberine Alkaloids
  • Cytokines
  • Interleukin-18
  • Interleukin-6
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Uric Acid
  • Superoxide Dismutase
  • palmatine

Grants and funding

The work was supported by Grants from National Natural Science Foundation of China (Nos. 82074082 & 82104472), Guangdong Natural Science Foundation (Nos. 2021A1515011490 & 2019A1515010819 & 2022A1515011706), Characteristic Cultivation Program for Subject Research of Guangzhou University of Chinese Medicine (No. XKP2019007), Guangzhou Liwan Disrtrict Science and Technology Project (No. 202201005), Key Program for Subject Research of Guangzhou University of Chinese Medicine (No. XK2019002) and Chinese Medicine Bureau of Guangdong Province (No. 20201134).