SUPPRESSION OF ARTHRITIS BY AN ACTIVE-CENTER ANALOG OF CU2ZN2-SUPEROXIDE DISMUTASE

The anti-arthritic and anti-inflammatory efficacy of CuPu(Py)(2) {[N,N'-bis(2-pyridylmethylene)-1,4-butanediamine] (N,N',N'', N''')}-Cu(II), a serum-stable active center analogue of Cu2Zn2-superoxide dismutase (SOD; EC 1.15.1.1), was tested in male DBA/1 x B10A (4R) mice suffering from potassium-peroxochromate-induced (PIA) or collagen type II-induced arthritis (CIA). Parameters including the arthritis index, the plasma SOD activity, and the inhibition of phagocytic responses in unseparated blood were used for the assessment of disease activity. A dose-dependent suppression of arthritis was noted in both models. The ED(50) was 2.5+/-0.4 mu mol/kg/day of CuPu(Py)(2) for PIA and 4.0+/-1.1 mu mol/kg/day for CIA. The arthritis index correlated with both the levels of reactive oxygen species (ROS) generated by phorbol ester-activated neutrophils and monocytes in unseparated blood (r = 0.892) and the SOD-like activity in plasma (r = 0.857). CuPu(Py)(2) inhibited also the lipoplysaccharide-induced release of tumor necrosis factor alpha from human monocytes and neutrophils in a dose-dependent manner. Unlike SOD, which exerts successful anti-rheumatic activity mainly upon intra-articular injection, the SOD-mimic CuPu(Py)(2) can be applied systemically. Non-proteinaceous low molecular weight antioxidases may well be suited to control oxidative stress-derived damage in rheumatic diseases by modulation of ROS-dependent signal transduction pathways.