Amelioration of joint disease in a rat model of collagen-induced arthritis by M40403, a superoxide dismutase mimetic.
OBJECTIVE
To investigate the effects of M40403, a synthetic mimetic of superoxide dismutase (SOD), on collagen-induced arthritis (CIA) in rats.


METHODS
CIA was elicited in Lewis rats by intradermal injection of 100 microl of an emulsion of bovine type II collagen (CII) in Freund's incomplete adjuvant at the base of the tail. A second injection was given on day 21.


RESULTS
Immunization induced an erosive arthritis of the hind paws. Macroscopic evidence of CIA first appeared as periarticular erythema and edema in the hind paws by days 24-26 after the first injection, with a 100% incidence by days 27. Severity progressed over a 35-day period. Radiography revealed soft tissue swelling and focal resorption of bone, together with osteophyte formation in the tibiotarsal joint. Histopathologic features included erosion of the articular cartilage at the joint margins and subchondral bone resorption associated with bone-derived multinucleated cell-containing granulomatous lesions. Treatment with M40403 (2-10 mg/kg/day) starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26-35 and improved the histologic findings in the joint and paw. Immunohistochemical analysis for nitrotyrosine (a marker of peroxynitrite formation) and poly(ADP-ribose) polymerase (PARP; a nuclear enzyme activated by DNA single-strand damage) revealed positive staining in the inflamed joints of CII-treated rats, suggestive of the formation of peroxynitrite and DNA damage, both of which were markedly reduced by M40403 treatment. Radiographic evidence of protection from bone resorption, osteophyte formation, and soft tissue swelling was apparent in the tibiotarsal joints of M40403-treated rats. Arthritic rats treated with M40403 gained weight at the same rate and to the same extent as normal, nonarthritic rats.


CONCLUSIONS
This study shows that a low molecular weight mimetic of SOD, M40403, attenuates the degree of chronic inflammation, tissue damage, and bone damage associated with CIA in the rat, and supports the possible use of SOD mimetics as therapeutic agents for the management of chronic diseases such as rheumatoid arthritis.
Salvemini
D
D
MetaPhore Pharmaceuticals, St. Louis, Missouri 63114, USA. dsalvemini@metaphore.com
Mazzon
E
E
Dugo
L
L
Serraino
I
I
De Sarro
A
A
Caputi
A P
AP
Cuzzocrea
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D000917:Antibody Formation / Q000187:drug effects; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001175:Arthrography; D003094:Collagen; D024161:Collagen Type XI; D004195:Disease Models, Animal; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008297:Male; D008345:Manganese; D008970:Molecular Weight; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013482:Superoxide Dismutase / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D024161:Collagen Type XI; D007375:Interleukin-1; D009942:Organometallic Compounds; C066455:PARP protein, Bos taurus; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C121876:imisopasem manganese; C002744:3-nitrotyrosine; D014443:Tyrosine; D008345:Manganese; D003094:Collagen; D013482:Superoxide Dismutase