Amelioration of rat adjuvant arthritis by therapeutic treatment with bindarit, an inhibitor of MCP-1 and TNF-α production

Abstract

Results obtained indicate that bindarit beneficial effects in experimental arthritis are correlated to MCP-1 and TNF-alpha inhibition and suggest that the control of cytokines and chemokines production can have considerable relevance as regards strategies for the treatment of chronic inflammatory diseases.

Chemokines and their receptors in rheumatoid arthritis: Future targets?

“…Kraan et al showed that IL-8/ CXCL8 was increased in the involved joints compared with the uninvolved joints of patients with RA (25). In a study by Taylor et al, TNF␣ blockade in patients with RA resulted in decreased 111 In-labeled granulocyte migration into affected joints as well as a reduction in the expression of IL-8/CXCL8 in the ST (26). Chemokine networks exist in the RA joint, so that RANTES/CCL5, monocyte chemoattractant protein 1 (MCP-1)/CCL2, or SDF-1/CXCL12 up-regulates RA ST fibroblast expression of IL-8/CXCL8, indicating that chemokines can regulate the expression of other chemokines in the joint (27).…”

“…Injection of neutralizing MCP-1/CCL2 resulted in reduced macrophage numbers and arthritis in rats with CIA (110). Bindarit, an indazolic derivative inhibitor of TNF␣ and MCP-1/CCL2, inhibited rat AIA (111). Injection of anti-MCP-1/CCL2 preventively resulted in decreased influx of 111 In-labeled T cells into the rat streptococcal cell wall antigeninduced arthritic joint (112).…”

Modern Pharmacological Approaches to Therapies: Substances Tested in Animal Models of Rheumatoid Arthritis

“…This suggests that MCP-1 is mainly produced locally by activated cells, where it may exacerbate and sustain inflammation by attracting proinflammatory leukocytes, predominantly monocytes (Stankovic et al, 2009). Substances that can suppress the production of MCP-1 have shown beneficial effects in animal models of arthritis (Guglielmotti et al, 2002;Inoue et al, 2001). A completely different picture was revealed for IL-4.…”

An engineered monomer of CCL2 has anti-inflammatory properties emphasizing the importance of oligomerization for chemokine activity in vivo

“…Similarly, gene transfer of a truncated variant, 7ND, was shown to be efficacious in a mouse model of atherosclerosis [12,13]. Interestingly, the small molecule, bindarit, which specifically decreases levels of CCL2 expression [14], was efficacious in vivo in models of acute pancreatitis [15], lupus [16], and adjuvant-induced arthritis [17], despite its relatively low potency in vitro. However, although blockade of CCR2 with a mAb in the model of collagen-induced arthritis prevented disease when administered prophylactically, it aggravated joint inflammation when given in a therapeutic regimen [18].…”