Benzylideneacetophenone Derivative Alleviates Arthritic Symptoms via Modulation of the MAPK Signaling Pathway

Abstract

The benzylideneacetophenone derivative 3-(4-hydroxy-3-methoxy-phenyl)-1-{3-[1]-phenyl}-propenone (JC3 dimer) was synthesized through the dimerization of JC3. To investigate the inhibitory effects of JC3 dimer, the carrageenan/kaolin (C/K)-induced knee arthritis rat model was used in vivo and rheumatoid arthritis (RA) patient-derived fibroblast-like synoviocytes (FLS) were usedin vitro. In the C/K rat model, JC3 dimer was given after arthritis induction for 6 days at the concentrations of 1, 5, or 10 mg/kg/day. Manifestation of arthritis was evaluated using knee thickness, weight distribution ratio (WDR), and squeaking test. The levels of prostaglandin E-2(PGE(2)), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha in the serum of JC3 dimer-treated arthritic rats were also analyzed. Histological examination of the knee joints was also done. For the FLS, the cells were stimulated using IL-1 beta and concentrations of 1, 5, and 10 mu g/mL JC3 dimer were used. The levels of IL-8, IL-6, and PGE(2)were measured in stimulated FLS treated with JC3 dimer. At days 5 to 6 after arthritis induction, JC3 dimer treatment significantly decreased arthritic symptoms and reduced the inflammation in the knee joints in the histology of knee tissues in C/K-arthritic rats. In stimulated FLS, JC3 dimer suppressed the increase of IL-8, IL-6, and PGE(2). These findings suggest that JC3 dimer has suppressive effects on arthritis, and that JC3 dimer can be a potential agent for arthritis therapy.