Effects of selective iNOS inhibition on type II collagen-induced arthritis in mice.
Nitric oxide as well as prostaglandins has been reported to play an important role in inflammatory diseases including arthritis. In the present study, the effects of iNOS inhibition on development of disease were examined in type II collagen-induced arthritis (CIA) in male DBA/1J mice. From 4 weeks after the first immunization with bovine type II collagen, 1400W (10 mg/kg/day, p.o.), a selective iNOS inhibitor, indomethacin (1 mg/kg/day, p.o.), a cyclooxygenase (COX) inhibitor, or 1400W + indomethacin was administered for 8 weeks. Immunization with type II collagen evoked arthritic inflammation of paws and bone destruction accompanied by increases in urinary nitrite/nitrate (NOx) excretion, plasma NOx and PGE2 levels. Administration of 1400W reduced urinary NOx excretion and increased plasma PGE2 levels, while it had no effect on arthritic inflammation or bone destruction. Indomethacin slightly reduced the inflammatory signs and bone destruction with marked reduction of plasma PGE2. Combination of 1400W and indomethacin reduced urinary NOx and PGE2 levels, and showed greater amelioration of inflammatory signs and bone destruction than either alone. In conclusion, 1400W, a selective iNOS inhibitor, failed to prevent CIA probably due to its increasing effect on PGE2 production, but showed a synergistic ameliorative effect in combination with indomethacin.
Sakaguchi
Yasue
Y
Kobuchisawa Laboratories, Fuji Biomedix Co., Ltd., 10221, Kobuchisawa-cho, Kitakoma-gun, Yamanashi 408-0044, Japan. ysakaguchi@fbm.co.jp
Shirahase
Hiroaki
H
Ichikawa
Atsuko
A
Kanda
Mamoru
M
Nozaki
Yoshihiro
Y
Uehara
Yoshio
Y
D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000906:Antibodies / Q000032:analysis; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D001596:Benzylamines / Q000627:therapeutic use*; D024043:Collagen Type II / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005528:Foot / Q000473:pathology; D007213:Indomethacin / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007596:Joints / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood / Q000652:urine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011859:Radiography
D000578:Amidines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D001596:Benzylamines; D024043:Collagen Type II; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D015232:Dinoprostone; D007213:Indomethacin