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

S. Cuzzocrea, P.K. Chatterjee, E. Mazzon, M.C. McDonald, L. Dugo, R. Di Paola, I. Serraino, D. Britti, A.P. Caputi, C. Thiemermann

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)119-129
Number of pages11
JournalEuropean Journal of Pharmacology
Volume453
Issue number1
DOIs
Publication statusPublished - Oct 2002

Fingerprint

Experimental Arthritis
Nitric Oxide Synthase Type II
Rodentia
Collagen Type II
Freund's Adjuvant
Joints
Poly(ADP-ribose) Polymerases
GW 274150
Bone Resorption
Arthritis
Staining and Labeling
Intradermal Injections
Erythema
Emulsions

Keywords

  • Arthritis, collagen-induced
  • GW274150
  • Nitric oxide (NO) synthase, inducible

Cite this

Cuzzocrea, S. ; Chatterjee, P.K. ; Mazzon, E. ; McDonald, M.C. ; Dugo, L. ; Di Paola, R. ; Serraino, I. ; Britti, D. ; Caputi, A.P. ; Thiemermann, C. / Beneficial effects of GW274150, a novel, potent and selective inhibitor of iNOS activity, in a rodent model of collagen-induced arthritis. In: European Journal of Pharmacology. 2002 ; Vol. 453, No. 1. pp. 119-129.
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abstract = "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.",
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author = "S. Cuzzocrea and P.K. Chatterjee and E. Mazzon and M.C. McDonald and L. Dugo and {Di Paola}, R. and I. Serraino and D. Britti and A.P. Caputi and C. Thiemermann",
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Beneficial effects of GW274150, a novel, potent and selective inhibitor of iNOS activity, in a rodent model of collagen-induced arthritis. / Cuzzocrea, S.; Chatterjee, P.K.; Mazzon, E.; McDonald, M.C.; Dugo, L.; Di Paola, R.; Serraino, I.; Britti, D.; Caputi, A.P.; Thiemermann, C.

In: European Journal of Pharmacology, Vol. 453, No. 1, 10.2002, p. 119-129.

Research output: Contribution to journalArticleResearchpeer-review

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

VL - 453

SP - 119

EP - 129

JO - European Journal of Pharmacology

T2 - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 1

ER -