Original ArticleInhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway
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.
References (46)
- et al.
The efficacy and mechanism action of RvCSd, a new herbal agent, on immune suppression and cartilage protection in a mouse model of rheumatoid arthritis
J Pharmacol Sci
(2009) - et al.
A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes
Osteoarthritis Cartilage
(2008) - et al.
Artesunate protects sepsis model mice challenged with Staphylococcus aureus by decreasing TNF-alpha release via inhibition TLR2 and Nod2 mRNA expressions and transcription factor NF-kappaB activation
Int Immunopharmacol
(2010) - et al.
Inhibitory effects of a traditional Chinese herbal formula TBL-II on type II collagen-induced arthritis in mice
J Ethnopharmacol
(2011) - et al.
Markedly elevated serum MMP-9 (gelatinase B) levels in rheumatoid arthritis: a potentially useful laboratory marker
Clin Immunol Immunopathol
(1996) Molecular mechanism of transcriptional activation of human gelatinase B by proximal promoter
Cancer Lett
(1996)- et al.
Prevalence of arthritis: analysis of data from the US Behavioral Risk Factor Surveillance System, 1996-99
J Rheumatol
(2002) - et al.
Evidence that cytokines play a role in rheumatoid arthritis
J Clin Invest
(2008) - et al.
Interleukin-10 and articular cartilage: experimental therapeutical approaches in cartilage disorders
Curr Gene Ther
(2009) - et al.
mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis
Mol Med
(2010)
Modulation of interleukin-6 and matrix metalloproteinase 2 expression in human fibroblast-like synoviocytes by functional ionotropic glutamate receptors
Arthritis Rheum
Therapeutic strategies for rheumatoid arthritis
N Engl J Med
Therapeutic strategies for rheumatoid arthritis
Nat Rev Drug Discov
Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy
Microbiol Rev
Artesunate for the treatment of severe falciparum malaria
N Engl J Med
A pilot study of the therapeutic efficacy and mechanism of artesunate in the MRL/lpr murine model of systemic lupus erythematosus
Cell Mol Immunol
Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes
Rheumatology (Oxford)
The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1alpha in human rheumatoid arthritis fibroblast-like synoviocyte
Rheumatol Int
Membrane complement regulators protect against the development of type II collagen-induced arthritis in rats
Arthritis Rheum
Amelioration of collagen-induced arthritis in rats by nanogold
Arthritis Rheum
Anti-arthritis effects of vitamin K(2) (menaquinone-4)–a new potential therapeutic strategy for rheumatoid arthritis
FEBS J
Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction
Arthritis Rheum
The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease
Cell Mol Immunol
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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.
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Y.L., S.W., and Y.W. contributed equally to this work.