Abstract
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.
Highlights
Rheumatoid arthritis (RA) is a response of joint tissues to joint deformation, trauma or biochemical, genetic, or intracellular factors [2, 11]
We examined the effect of JC3 on weight distribution ratios (WDR) of hind paws of rats with carrageenan/kaolin-induced arthritis (Fig. 3b)
When we examined the effect of JC3, we found it inhibited IL-1β-induced IL-8 secretion in fibroblastlike synoviocytes (FLS) (Fig. 5c), which suggested JC3 inhibits neovascularization in the inflamed joints of arthritic rats
Summary
Rheumatoid arthritis (RA) is a response of joint tissues to joint deformation, trauma or biochemical, genetic, or intracellular factors [2, 11]. Proliferative fibroblast-like synoviocytes (FLSs) play key roles in joint damage and in the propagation of inflammation because they produce considerable amounts of. Inhibition of carrageenan/kaolin-induced arthritis in rats proinflammatory mediators, such as interleukin-6 (IL-6) and prostaglandin E2 (PGE2) [16]. RA progression is associated with increased cytokine levels of IL-1β, which is produced by macrophages and dendritic cells [20]. Because IL-1β is believed to play a crucial role in synovial inflammation, elevating IL-1β levels in FLSs has been used to mimic the synovial proliferation that occurs in RA [13]. IL-1β is known to prompt the over expressions of proinflammatory factors in many cell types [3]. The nonsteroidal anti-inflammatory agents used to treat RA are known to have harmful effects, in the gastrointestinal tract, and there is a need for anti-inflammatory drugs with fewer side effects [8, 12]
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