TY - JOUR
T1 - Beneficial effects of GW274150, a novel, potent and selective inhibitor of iNOS activity, in a rodent model of collagen-induced arthritis
AU - Cuzzocrea, S.
AU - Chatterjee, P.K.
AU - Mazzon, E.
AU - McDonald, M.C.
AU - Dugo, L.
AU - Di Paola, R.
AU - Serraino, I.
AU - Britti, D.
AU - Caputi, A.P.
AU - Thiemermann, C.
PY - 2002/10
Y1 - 2002/10
N2 - 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.
AB - 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.
KW - Arthritis, collagen-induced
KW - GW274150
KW - Nitric oxide (NO) synthase, inducible
U2 - doi:10.1016/S0014-2999(02)02338-5
DO - doi:10.1016/S0014-2999(02)02338-5
M3 - Article
SN - 0014-2999
VL - 453
SP - 119
EP - 129
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -