Allylpyrocatechol attenuates collagen-induced arthritis via attenuation of oxidative stress secondary to modulation of the MAPK, JAK/STAT, and Nrf2/HO-1 pathways

Abstract

Rheumatoid arthritis (RA), an inflammatory autoimmune disorder is characterized by synovial hyperplasia and bony destruction. The pathogenesis of RA includes redox dysregulation, concomitant with increased levels of pro-inflammatory mediators. As the ability of Allylpyrocatechol (APC), a phytoconstituent of Piper betle leaves to alleviate oxidative stress has been demonstrated in patients with RA, its anti-arthritic activity was evaluated in an animal model of arthritis, along with establishment of the underlying mechanism(s) of action. The animal model was established by immunizing rats with bovine collagen type II (CII) followed by lipopolysaccharide, along with a booster dose of CII on day 15. Rats were treated with APC or Methotrexate (MTX) from days 11 to 27, wherein paw edema, radiography, histopathology and markers of inflammation were evaluated. The pro/anti-inflammatory signaling pathways were studied in a RAW264.7 macrophage cell line. APC prevented the progression of arthritis as evident from the reduction in paw edema, attenuation of damage to bones and cartilage as evident by radiography as also histopathology. Additionally, there was reduction in the levels of pro-inflammatory cytokines (TNF-α and IL-6) and restoration of the redox balance. Importantly, MTX ameliorated the features of arthritis, but not the associated oxidative stress. In RAW264.7, APC inhibited generation of nitric oxide and pro-inflammatory cytokines (TNF-α, IL-6 and IL-12p40), modulated the phosphorylation of pro-inflammatory (ERK1/2, SAPK/JNK, and JAK/STAT) and cytoprotective (Nrf2, HO-1) signaling pathways. Taken together, APC controlled the development of arthritis possibly via modulation of signaling pathways and deserves further consideration in the therapy for RA.