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 sufferin g from potassium-peroxochromate-induced (PIA) or collagen type II-indu ced arthritis (CIA). Parameters including the arthritis index, the pla sma SOD activity, and the inhibition of phagocytic responses in unsepa rated blood were used for the assessment of disease activity. A dose-d ependent 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 m ol/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 SO D-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-ar ticular injection, the SOD-mimic CuPu(Py)(2) can be applied systemical ly. Non-proteinaceous low molecular weight antioxidases may well be su ited to control oxidative stress-derived damage in rheumatic diseases by modulation of ROS-dependent signal transduction pathways.