Inhibition of Carrageenan/Kaolin-Induced Arthritis in Rats and of Inflammatory Cytokine Expressions in Human IL-1β-Stimulated Fibroblast-like Synoviocytes by a Benzylideneacetophenone Derivative

摘要

The benzylideneacetophenone derivative JC3 [(2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one] (JC3) was synthesized by modifying yakuchinone B obtained from the seeds of Alpinia oxyphylla, a member of the ginger family (Zingiberaceae), which are widely used as a folk remedy and as an anti-inflammatory. The aim of this study was to investigate the anti-arthritic effects of JC3 in rat models of carrageenan-induced paw pain and carrageenan/kaolin-induced knee arthritis. The anti-nociceptive effect of JC3 was assessed by measuring paw withdrawal pressure thresholds using an analgesy-meter. Arthritic symptoms in our monoarthritic rat model were evaluated using weight distribution ratios (WDR), paw thicknesses, and serum prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and vascular endothelial growth factor (VEGF) levels (determined by ELISA). Histological analyses of knee joints were performed after injecting JC3 intraperitoneally into rats before carrageenan treatment at 5 or 10 mg/kg/day for 6 days. The anti-inflammatory effects of JC3 were investigated in vitro using interleukin-1beta (IL-1β)-stimulated fibroblast-like synoviocytes (FLS) derived from arthritis patients. PGE2, IL-6, and IL-8 levels were measured after treating FLS with JC3. In arthritis-induced rats, JC3 treatment significantly decreased nociceptive and arthritic symptoms at days 5 to 6 after carrageenan/kaolin injection. Histological staining of knee tissue showed that JC3 significantly reduced inflammatory areas in the knee joints. Furthermore, JC3 inhibited the expressions of IL-6 and IL-8 in FLS cells at concentrations of 5–10 μg/ml and decreased PGE2 levels in FLS cells. These findings suggest JC3 has anti-arthritic effects in in vivo and in vitro, and that it might be useful for the treatment of arthritis.