Suppression of arthritis by an active center analogue 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 ED50 was 2.5 +/- 0.4 mumol/kg/day of CuPu(Py)2 for PIA and 4.0 +/- 1.1 mumol/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.
Deutsches RheumaForschungsZentrum, Berlin, Germany.
R
R
Miesel
A
A
Dietrich
B
B
Brandl
N
N
Ulbrich
M
M
Kurpisz
H
H
Kröger
D000818:Animals; D001168:Arthritis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology*; D002840:Chromates / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010545:Peroxides / Q000494:pharmacology; D012545:Schiff Bases / Q000494:pharmacology / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000097:blood / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects
D002840:Chromates; D009942:Organometallic Compounds; D010545:Peroxides; D012545:Schiff Bases; D014409:Tumor Necrosis Factor-alpha; C019537:potassium tetraperoxochromate; D003094:Collagen; C064004:N,N'-bis(2-pyridylmethylene)-1,4-butanediamine (N,N',N'',N''')-Cu(II)diperchlorate; D013482:Superoxide Dismutase