M40403 is a proprietary compound of Metaphore Pharmaceuticals, Inc. Support and material for this study were supplied by Metaphore.
Article first published online: 2 JUN 2005
Copyright © 2005 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 52, Issue 6, pages 1929–1940, June 2005
How to Cite
Cuzzocrea, S., Mazzon, E., Paola, R. D., Genovese, T., Muià, C., Caputi, A. P. and Salvemini, D. (2005), Effects of combination M40403 and dexamethasone therapy on joint disease in a rat model of collagen-induced arthritis. Arthritis & Rheumatism, 52: 1929–1940. doi: 10.1002/art.21044
Address reprint requests to Alan W. Dunton, MD, Metaphore Pharmaceuticals, One Bridge Plaza, Suite 500, Fort Lee, NJ 07024. E-mail: firstname.lastname@example.org.
- Issue published online: 2 JUN 2005
- Article first published online: 2 JUN 2005
- Manuscript Accepted: 18 FEB 2005
- Manuscript Received: 18 OCT 2004
To investigate the effects of combination therapy with M40403, a superoxide dismutase mimetic (SODm), and dexamethasone (DEX) on collagen-induced arthritis (CIA) in rats.
CIA was elicited in Lewis rats by an intradermal injection of 100 μl 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.
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.
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.