PD184352 exerts anti-inflammatory and antioxidant effects by promoting activation of the Nrf2/HO-1 axis

Biochem Pharmacol. 2023 May:211:115542. doi: 10.1016/j.bcp.2023.115542. Epub 2023 Apr 6.

Abstract

Osteoarthritis (OA) is a disabling joint disease characterized by cartilage degeneration. Reactive oxygen species (ROS)-induced oxidative stress is an important cause of early chondrocyte death. For this reason, we investigated PD184352, a small molecule inhibitor with potential anti-inflammatory and antioxidant activity. We evaluated the protective effect of PD184352 against destabilized medial meniscus (DMM)-induced OA in mice. The knee joints of the PD184352-treated group had higher Nrf2 expression and milder cartilage damage. Moreover, in in vitro experiments, PD184352 suppressed IL-1β-induced NO, iNOS, PGE2 production, and attenuated pyroptosis. PD184352 treatment promoted antioxidant protein expression and reduced the accumulation of ROS by activating the Nrf2/HO-1 axis. Finally, the anti-inflammatory and antioxidant effects of PD184352 were shown to be partially dependent on Nrf2 activation. Our study reveals the potential role of PD184352 as an antioxidant and provides a new strategy for OA treatment.

Keywords: Inflammation; Osteoarthritis; Oxidative stress; PD184352; Pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use
  • Antioxidants* / metabolism
  • Chondrocytes
  • Interleukin-1beta / metabolism
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Osteoarthritis* / drug therapy
  • Osteoarthritis* / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • Antioxidants
  • Reactive Oxygen Species
  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • NF-E2-Related Factor 2
  • Anti-Inflammatory Agents
  • Interleukin-1beta