REACTIVITY OF AN ACTIVE-CENTER ANALOG OF CU2ZN2SUPEROXIDE DISMUTASE IN MURINE MODEL OF ACUTE AND CHRONIC INFLAMMATION

The antiinflammatory efficacy of CuPu(Py)2 ({[N,N]-bis(2-pyridylmethylene)-1,4-butanediamine] (N,N',N'',N''')}-Cu2+), a serum stable active center analog of Cu2Zn2superoxide dismutase (SOD), was tested in vitro and in vivo in male Wistar rats suffering from potassium peroxochromate-induced inflammation. Parameters including Tc-99m gamma-scintigraphic imaging, the arthritis score, the plasma superoxide dismutase activity, the inhibition of plasma sulfhydryl depletion as well as mitogenic and phagocytic responses were used to quantify the disease activity. All parameters improved impressively during the treatment with CuPu(Py)2 and resembled those of healthy animals after 21 days. The arthritis score was inhibited by 80% (P > 0.001) and the plasma SOD activity enhanced by 380% (P > 0.001). The depletion of plasma sulfhydryls and the leukocytic responses to concanavalin A, tetradecanoylphorbolacetate, and lipopolysaccharide were significantly reduced (P > 0.001) and correlated well with the arthritis score. The collapse of antioxidant defenses in human plasma as well as the depolymerization of hyaluronic acid was mimicked in vitro and successfully inhibited by CuPu(Py)2. Oxidant-induced injury of plasma components during the aqueous decay of potassium peroxochromate were demonstrated to activate the oxidative burst of phagocytes in human blood. The role of impaired pro- and antioxidant balances in the etiology of inflammatory and autoimmune rheumatic diseases is discussed.