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, 42 (3), 928-936

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

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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

Bongjun Sur et al. Inflammation.

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.

Keywords: Anti-inflammatory; Arthritis; Benzylideneacetophenone derivative; Fibroblast-like synoviocytes.

Figures

Fig. 1
Fig. 1
Analgesic effect of JC3 in the carrageenan-induced hyperalgesia rat model. Hyperalgesia was induced by an intra-plantar injection of carrageenan (100 μL of 1% solution) into left hind paws. JC3 was administered (i.p.) 1 h before carrageenan injection. Nociceptive thresholds were determined by the Randall–Selitto test using a paw-pressure analgesy meter 3 h after carrageenan injection. NOR non-treated group, CON carrageenan-treated control group, CON+JC3_5 carrageenan-induced and 5 mg/kg JC3-treated groups, and CON+JC3_10 carrageenan-induced and 10 mg/kg JC3-treated group. Results are presented as means ± standard errors. Data analysis was performed using one-way ANOVA followed by Tukey’s post hoc test. **p < 0.01 vs. NOR group, #p < 0.05 vs. CON group.
Fig. 2
Fig. 2
Histological images of the knee joints of rat administered JC3 in the NOR (a), ART (b), ART+JC3_5 (c), and ART+JC3_10 (d) groups. e Histology scores were determined using a standardized scoring scale as described in “MATERIALS AND METHODS.” Tissues were stained with hematoxylin and eosin (HE). Results are presented as means ± standard errors. ***p < 0.005 vs. the NOR group and #p < 0.05 vs. the ART group.
Fig. 3
Fig. 3
Assessments of anti-arthritic activity in the rat model of carrageenan/kaolin-induced arthritis. a Thicknesses of knees, b weight distribution ratios (WDRs), and c squeaking scores, indicating arthritis severity. Results are presented as means ± standard errors. ***p < 0.005 vs. the NOR group and #p < 0.05 and ##p < 0.01 vs. the ART group.
Fig. 4
Fig. 4
Effects of JC3 on the ELISA determined levels of the pro-inflammatory mediators TNF-α (a), IL-6 (b), PGE2 (c), and VEGF (d) in serum of the rat model of carrageenan/kaolin-induced arthritis. Results are presented as means ± standard errors. ***p < 0.005 vs. the NOR group and #p < 0.05 and ##p < 0.01 vs. the ART group.
Fig. 5
Fig. 5
Effects of JC3 on the ELISA determined levels of the pro-inflammatory mediators IL-6 (a) and PGE2 (b), and on the levels of IL-8 (angiogenic mediator) (c) in FLS cells. Results are presented as means ± standard errors. ***p < 0.001 vs. nontreated controls, #p < 0.05 and ###p < 0.005 vs. IL-1β-treated cells.

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