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Updated: Aug 22, 2026
Murine Model of Epicutaneously-Induced Immunomodulation
Published on: June 24, 2025
Effects of selective iNOS inhibition on type II collagen-induced arthritis in mice
Yasue Sakaguchi1, Hiroaki Shirahase, Atsuko Ichikawa
1Kobuchisawa Laboratories, Fuji Biomedix Co., Ltd., 10221, Kobuchisawa-cho, Kitakoma-gun, Yamanashi 408-0044, Japan. ysakaguchi@fbm.co.jp
Abstract:
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.
Insights
Selective iNOS inhibition alone did not prevent collagen-induced arthritis in mice. However, combining iNOS inhibition with a COX inhibitor synergistically reduced arthritis inflammation and bone destruction.
Area of Science:
- Immunology
- Pharmacology
Background:
- Nitric oxide and prostaglandins are key mediators in inflammatory diseases like arthritis.
- Understanding their specific roles is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the impact of inhibiting inducible nitric oxide synthase (iNOS) on the progression of collagen-induced arthritis (CIA).
- To evaluate the therapeutic potential of a selective iNOS inhibitor, 1400W, alone and in combination with indomethacin, a cyclooxygenase (COX) inhibitor.
Main Methods:
- Male DBA/1J mice were immunized to induce CIA.
- Mice received daily oral administration of 1400W (selective iNOS inhibitor), indomethacin (COX inhibitor), or a combination for 8 weeks.
- Arthritic inflammation, bone destruction, urinary nitrite/nitrate (NOx), plasma NOx, and PGE2 levels were assessed.
Main Results:
- 1400W administration decreased urinary NOx but increased plasma PGE2, without affecting arthritis severity or bone destruction.
- Indomethacin showed modest reduction in inflammation and bone destruction, with a significant decrease in plasma PGE2.
- The combination of 1400W and indomethacin demonstrated enhanced amelioration of inflammatory signs and bone destruction compared to either agent alone, alongside reduced NOx and PGE2 levels.
Conclusions:
- Selective iNOS inhibition with 1400W alone did not prevent CIA, potentially due to increased PGE2 production.
- Combination therapy with a COX inhibitor (indomethacin) yielded synergistic therapeutic effects in managing CIA, suggesting a complex interplay between iNOS and COX pathways in arthritis pathogenesis.
