Amelioration of rat adjuvant arthritis by therapeutic treatment with bindarit, an inhibitor of MCP-1 and TNF-alpha production.
OBJECTIVE
This study was designed to evaluate therapeutic effects of bindarit, an indazolic derivative able to inhibit monocyte chemoattractant protein-1 (MCP-1) production, in adjuvant induced arthritis in rats.


METHODS
Arthritis was induced by Freund's complete adjuvant injection. Bindarit was given as a 0.5% medicated diet starting on day 11 after adjuvant injection. The course of arthritis was monitored by sequential paw volume measurement and by radiologic and histologic evaluations. Human osteoblast cell line Saos-2 stimulated with Interleukin-1 (IL-1) was used to assess in vitro bindarit effect on MCP-1 release. In addition, in vivo effects of bindarit on cytokine production were studied in mice injected with lipopolysaccharide (LPS). Immune function studies were performed in mice by evaluating ex vivo antibody response to ovalbumin and splenocytes proliferation to Concanavalin A (Con A).


RESULTS
In adjuvant-induced arthritis in rats, bindarit possessed therapeutic activity resulting in a significant inhibition of paw inflammation. Evidence for a disease-modifying activity was also indicated by amelioration of radiologic alterations and by histological evaluation of joints. Additional evidence for beneficial effects in osseous inflammation was provided by an in vitro assay in which bindarit inhibited the release of MCP-1 from IL-1 stimulated osteoblast cells. Moreover, in a murine model of LPS-induced cytokine production bindarit reduced MCP-1 and tumor necrosis factor (TNF)-alpha increase without affecting IL-1 and IL-6 levels. Finally, the drug, given as a 0.5% medicated diet for 14 days, did not affect either anti-ovalbumin serum antibody production or splenocytes proliferative response in mice.


CONCLUSIONS
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.
Guglielmotti
A
A
Immunopharmacology Lab, ACRAF SpA - Angelini Ricerche, Rome, Italy. rd.guglielmotti@angelini.it
D'Onofrio
E
E
Coletta
I
I
Aquilini
L
L
Milanese
C
C
Pinza
M
M
D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D006614:Hindlimb / Q000473:pathology; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007191:Indazoles / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010006:Osteoblasts / Q000187:drug effects; D010047:Ovalbumin / Q000276:immunology; D011422:Propionates / Q000627:therapeutic use*; D011859:Radiography; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D018932:Chemokine CCL2; D016207:Cytokines; D007191:Indazoles; D008070:Lipopolysaccharides; D011422:Propionates; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin; C079489:bindarit