Effects of combination M40403 and dexamethasone therapy on joint disease in a rat model of collagen‐induced arthritis

Abstract

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 l 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.Conclusion. 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.

Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats

“…8A), although lower doses of DEX (0.1 and 0.5 mg) are sufficient in the rat to suppress joint destruction in chronic arthritis (Cuzzocrea et al, 2005) or zymosan-induced paw inflammation (Tegeder et al, 2001). Continuous intrathecal infusion of 0.02 mg/kg/day DEX for 7 days, beginning on the day of nerve injury, even led to an increase in pain sensitivity (Fig.…”

Secondary osteoporosis in collagen-induced arthritis rats

“…The induction of type II collagen (CII)-induced arthritis in female Lewis rats was based on the methods described by Cuzzocrea et al [13] and Shahi et al [14]. Briefly, we dissolved bovine CII (Sichuan University, China) in 0.05 M acetic acid at a concentration of 3 mg/ml by stirring the mixture overnight at 4 °C.…”

Acute and chronic anti-inflammatory properties of the stem bark aqueous and methanol extracts of Sclerocarya birrea (Anacardiaceae)

“…The use of anti-inflammatory drugs is known to be associated with various side effects, especially on gastrointestinal tract (Silverstein et al 2000;Cuzzocrea et al 2005;Dimo et al 2006). Therefore, the development of new therapies is required.…”