Effects of combination M40403 and dexamethasone therapy on joint disease in a rat model of collagen-induced arthritis.
OBJECTIVE
To investigate the effects of combination therapy with M40403, a superoxide dismutase mimetic (SODm), and dexamethasone (DEX) on collagen-induced arthritis (CIA) in rats.


METHODS
CIA was elicited in Lewis rats by an intradermal injection of 100 mul of an emulsion of bovine type II collagen (CII) in Freund's incomplete adjuvant (IFA) at the base of the tail. On day 21, a second injection of CII in IFA was administered at the base of the tail.


RESULTS
Lewis rats developed erosive arthritis of the hind paw when immunized with an emulsion of CII in IFA. The histopathology of CIA included erosion of the articular cartilage at the joint margins and subchondral bone resorption. Immunohistochemical analysis for nitrotyrosine, poly(ADP-ribose) polymerase (PARP), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) revealed positive staining in inflamed joints of collagen-treated rats. The combination therapy with M40403 2 mg/kg and DEX 0.01 mg/kg significantly reduced the development of the inflammatory process and reduced the degree of staining for iNOS, COX-2, nitrotyrosine, and PARP. No significant difference in the degree of staining between the combination therapy and the higher dose of DEX (0.1 mg/kg) was found. Furthermore, radiographic evidence of protection from bone resorption was apparent in the tibiotarsal joints of rats that received the combination therapy.


CONCLUSIONS
This study shows that combination therapy with M40403 and DEX reduced the degree of chronic inflammation and tissue and bone damage associated with CIA in the rat. It supports the possible use of SODm in combination with steroids to reduce the dose necessary and the side effects related to the use of steroids in the management of chronic diseases such as rheumatoid arthritis.
Cuzzocrea
Salvatore
S
University of Messina, Messina, Italy. salvator@unime.it
Mazzon
Emanuela
E
Paola
Rosanna Di
RD
Genovese
Tiziana
T
Muià
Carmelo
C
Caputi
Achille P
AP
Salvemini
Daniela
D
D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D001842:Bone and Bones / Q000378:metabolism; D003094:Collagen / Q000009:adverse effects; D003907:Dexamethasone / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D008297:Male; D008345:Manganese; D023421:Models, Animal; D009942:Organometallic Compounds / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D013482:Superoxide Dismutase / Q000032:analysis
D018501:Antirheumatic Agents; D009942:Organometallic Compounds; C121876:imisopasem manganese; D008345:Manganese; D003907:Dexamethasone; D003094:Collagen; D013482:Superoxide Dismutase