Beneficial effects of GW274150, a novel, potent and selective inhibitor of iNOS activity, in a rodent model of collagen-induced arthritis

• Published in: European journal of pharmacology Vol. 453; no. 1; pp. 119 - 129
• Main Authors: Cuzzocrea, Salvatore, Chatterjee, Prabal K, Mazzon, Emanuela, McDonald, Michelle C, Dugo, Laura, Di Paola, Rosanna, Serraino, Ivana, Britti, Domenico, Caputi, Achille P, Thiemermann, Christoph
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 18.10.2002; Elsevier
• Subjects: Animals; Arthritis; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Arthritis, Experimental - enzymology; Arthritis, Experimental - pathology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Collagen - toxicity; collagen-induced; Disease Models, Animal; Diseases of the osteoarticular system; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; GW274150; inducible; Inflammatory joint diseases; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric oxide (NO) synthase; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Pharmacology. Drug treatments; Sulfides - pharmacology; Sulfides - therapeutic use; Nitric oxide (NO) synthase; Arthritis; GW274150; Immunohistochemistry; Intraperitoneal administration; Pathogenesis; Diseases of the osteoarticular system; Autoimmune disease; Inflammatory joint disease; Cartilage; Histopathology; Mechanism of action; Immunopathology; Enzyme; Treatment efficiency; Rodentia; Antiinflammatory agent; Enzyme inhibitor; Inflammation; Nitric-oxide synthase; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Collagen; Rheumatoid arthritis; Oxidoreductases
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(02)02338-5

The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis. Collagen-induced arthritis was induced in wild-type mice (iNOS-WT) treated with GW274150, a novel, potent and selective inhibitor of iNOS activity, and in mice lacking the gene for iNOS (iNOS ‘knock-out’, iNOS-KO), by an intradermal injection of 100 μl of emulsion containing 100 μg of bovine type II collagen and complete Freund's adjuvant at the base of the tail. After 21 days, a second injection of type II collagen in complete Freund's adjuvant was administered. iNOS-WT mice developed erosive hind paw arthritis when immunised with type II collagen in complete Freund's adjuvant. Over a 35-day period, macroscopic clinical evidence of collagen-induced arthritis first appeared as periarticular erythema and oedema in the hind paws. By day 28, the incidence of collagen-induced arthritis was 100% in type II collagen-challenged iNOS-WT mice and the severity of collagen-induced arthritis progressed with radiographic evaluation revealing resorption of bone. Histopathology of collagen-induced arthritis mice demonstrated erosion of the cartilage at the joint margins. iNOS-WT mice treated with GW274150 (5 mg/kg, i.p. daily) starting at the onset of arthritis (day 23), and iNOS-KO mice showed a delay of the development of the clinical signs at days 24–35 and an improvement of the histological status in the knee and paw. Immunohistochemical analysis for nitrotyrosine and for poly(ADP-ribose) polymerase revealed positive staining in inflamed joints from type II collagen-treated iNOS-WT mice. The degree of staining for nitrotyrosine and poly(ADP-ribose) polymerase were markedly reduced in tissue sections obtained from type II collagen-treated iNOS-WT mice, who had received GW274150 and from iNOS-KO mice. Furthermore, radiographic signs of protection against bone resorption were present in the joints of iNOS-WT mice treated with GW274150 as well as in the joint from iNOS-KO mice. This study provides the first evidence that GW274150, a novel, potent and selective inhibitor of iNOS activity, attenuates the degree of chronic inflammation and tissue damage associated with collagen-induced arthritis in mice. Furthermore, these results suggest that the induction of iNOS and NO production are essential for the up-regulation of the inflammatory response during experimental collagen-induced arthritis.