Suppression of type II collagen-induced arthritis by a new isocoumarin, NM-3.
The anti-arthritic effect of NM-3, a new isocoumarin, was examined using a type II collagen-induced arthritis model for human rheumatoid arthritis in DBA/1J mice. NM-3 by oral administration suppressed dose-dependently (2-20 mg/kg/day) not only macroscopic changes such as erythema and swelling of limbs but also histopathologic changes and radiographic changes such as bone lesions. The efficacy of NM-3 was greater than those of disease-modifying anti-rheumatoid drugs (DMARDs), auranofin (40 mg/kg/day) and bucillamine (10 mg/kg/day). NM-3 failed to suppress carageenan-induced edema and to inhibit the activities of inflammation-related enzymes including cyclooxygenase-1 and -2, 5-lipoxygenase and phospholipase A2, suggesting that the mode of anti-arthritic action of NM-3 may be different from those of non-steroidal anti-inflammatory agents (NSAIDs). Since NM-3 inhibits angiogenesis in a mouse dorsal air-sac model, the observed anti-arthritic effect of NM-3 might be partly attributed to the antiangiogenic activity. Thus, NM-3 is a potential orally active therapeutic agent for the treatment of human rheumatoid arthritis.
Agata
N
N
Central Research Laboratories, Mercian Corp., Fujisawa, Japan. naokiagat@aol.com
Hirano
S
S
Abe
C
C
Nakashima
T
T
Tsuchiya
A
A
Kumagai
H
H
Isshiki
K
K
Yoshioka
T
T
Ishizuka
M
M
Takeuchi
T
T
D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D002351:Carrageenan; D024043:Collagen Type II / Q000276:immunology; D003374:Coumarins / Q000627:therapeutic use*; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005528:Foot / Q000000981:diagnostic imaging / Q000473:pathology; D007074:Immunoglobulin G / Q000378:metabolism; D049934:Isocoumarins; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009929:Organ Size / Q000187:drug effects; D011859:Radiography; D051381:Rats; D013154:Spleen / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology
D018501:Antirheumatic Agents; D024043:Collagen Type II; D003374:Coumarins; D007074:Immunoglobulin G; D049934:Isocoumarins; C453300:isocoumarin NM-3; D002351:Carrageenan