Suppression of arthritis by an active center analogue of Cu2Zn2-superoxide dismutase.

Abstract

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.

• Authors: R Miesel, A Dietrich, B Brandl, N Ulbrich, M Kurpisz, H Kröger
• Journal: Rheumatology international (Rheumatol Int) Vol. 14 Issue 3 Pg. 119-26 ( 1994) ISSN: 0172-8172 [Print] Germany
• PMID: 7839072 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Chromates
• Organometallic Compounds
• Peroxides
• Schiff Bases
• Tumor Necrosis Factor-alpha
• potassium tetraperoxochromate
• Collagen
• N,N'-bis(2-pyridylmethylene)-1,4-butanediamine (N,N',N'',N''')-Cu(II)diperchlorate
• Superoxide Dismutase

Topics

• Animals
• Arthritis (blood, chemically induced, drug therapy, enzymology)
• Chromates (pharmacology)
• Collagen (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Luminescent Measurements
• Male
• Mice
• Mice, Inbred DBA
• Organometallic Compounds (pharmacology, therapeutic use)
• Peroxides (pharmacology)
• Schiff Bases (pharmacology, therapeutic use)
• Superoxide Dismutase (biosynthesis, blood, drug effects)
• Tumor Necrosis Factor-alpha (biosynthesis, drug effects)