Elsevier

Translational Research

Volume 161, Issue 2, February 2013, Pages 89-98
Translational Research

Original Article
Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway

https://doi.org/10.1016/j.trsl.2012.06.001Get rights and content

Recent evidence indicates that the antimalarial agent artesunate (ART) has immunomodulatory properties that may be useful for treating rheumatoid arthritis (RA). However, the effects of ART on the RA animal model have not been described. The current study aimed to evaluate the antiarthritic effect of ART and explore the potential mechanism on type II collagen-induced arthritis (CIA) in rats. From the day of arthritis onset, rats were treated daily by gavage with leflunomide (Lef) or ART at a dosage of 10 mg/kg/d or 5 mg/kg/d, respectively, for 16 days. The severity of arthritis and levels of pro- and anti-inflammatory cytokines in site were measured. The expression and activity of metalloproteinase (MMP)-2 and MMP-9 were determined. The activation of nuclear factor kappa B and mitogen-activated protein kinase signaling pathways was investigated in rats with CIA and in Raw264.7 cells. Our results showed that ART treatment significantly attenuated inflammation symptoms and prevented cartilage and bone destruction. ART decreased expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-17α. Both expression and activity of MMP-9 were efficiently inhibited by ART. ART significantly inhibited the degradation of IκB and activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in rats with CIA and in lipopolysaccharide-stimulated Raw264.7 cells. The present study demonstrated that ART ameliorated rat CIA. The antiarthritic effect might be achieved by inhibiting the action of proinflammatory cytokines and the activity of MMP-9 via suppression of nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. These results show that ART may be used as an adjuvant therapy for patients with RA.

Section snippets

Chemicals and reagents

ART and leflunomide (Lef) tablets were produced by Guilin Pharmaceutical Factory (Guilin, Guangxi, PR China) and American Cinkate Corporation (Oak Park, Ill), respectively. The drugs were prepared with 0.5% carboxymethylcellulose sodium and stored at 4°C. Bovine type II collagen (2 mg/mL, dissolved in 0.05 mol/L acetic acid) and Freund’s incomplete adjuvants (4 mg/mL) were purchased from Chondrex Inc (Redmond, Wash). Primary antibodies against MMPs (MMP-2 and MMP-9) were purchased from

Effect of ART on the symptoms of CIA in rats

We tested the therapeutic efficacy of ART on CIA in rats. Onset generally occurred approximately 10 days after the immunization. Clinical manifestations, such as functional impairment and swollen red paws, were observed (Fig 1A). The inflammation score and hind-paw volume were typically increased and reached a plateau 7 days after arthritis onset.

After drug treatment for 16 days, both inflammation score and hind-paw volume were significantly decreased. As shown in Fig 1B, inflammation score in

Discussion

In RA, the cascade of biologic pathways that involve acute and chronic inflammation, the immune response, and MMP biochemistry causes the complicated and multifaceted symptoms and pathologic features.20 Thus, drugs for RA therapy should rapidly control inflammation, halt the progressive joint destruction, and be safe to use over an extended period. The present study showed that ART, the most effective and safe drug for the treatment of severe and chloroquine-resistant malaria, provided an

Conclusions

The present study demonstrated that ART exhibited important immunomodulatory effects on rat CIA. ART not only ameliorated the symptoms of arthritis but also prevented joint damage. The antiarthritic effects of ART might be achieved by inhibiting the action of proinflammatory cytokines and the activity of MMP-9 via suppression of NF-κB and MAPK signaling pathway. Further studies are warranted to test whether ART could be used as an adjuvant therapy for patients with RA.

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    This study was supported by National Natural Science Foundation of China (No. 31070924 and 81173056), Projects of International Cooperation and Exchanges, Science and Technology Planning Project of Guangdong Province, China (No. 1011420600004), and Research Fund for the Doctoral Program of Higher Education of China (No. 20100171110052).

    The authors have no conflicts of interest to declare. All authors have read the Journal’s policy on disclosure of potential conflicts of interest.

    Y.L., S.W., and Y.W. contributed equally to this work.

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