Late administration of Mn porphyrin-based SOD mimic enhances diabetic complications

Mn(III) N-alkylpyridylporphyrins (MnPs) have demonstrated protection in various conditions where increased production of reactive oxygen/reactive nitrogen species (ROS/RNS), is a key pathological factors. MnPs can produce both pro-oxidative and antioxidative effects depending upon the cellular redox environment that they encounter. Previously we reported (Free Radic. Res. 39: 81-8, 2005) that when the treatment started at the onset of diabetes, Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin, MnTM-2-PyP5+ suppressed diabetes-induced oxidative stress. Diabetes, however, is rarely diagnosed at its onset. The aim of this study was to investigate if MnTM-2-PyP5+ can suppress oxidative damage and prevent diabetic complications when administered more than a week after the onset of diabetes. Diabetes was induced by streptozotocin. The MnP-based treatment started 8 days after the onset of diabetes and continued for 2 months. The effect of the treatment on activities of glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, and glyoxalases I and II as well as malondialdehyde and GSH/GSSG ratio were determined in kidneys. Kidney function was assessed by measuring lysozyme and total protein in urine and blood urea nitrogen. Vascular damage was evaluated by assessing vascular reactivity. Our data showed that delayed administration of MnTM-2-PyP5+ did not protect against oxidative damage and did not prevent diabetic complications. Moreover, MnTM-2-PyP5+ contributed to the kidney damage, which seems to be a consequence of its pro-oxidative action. Such outcome can be explained by advanced oxidative damage which already existed at the moment the therapy with MnP started. The data support the concept that the overall biological effect of a redox-active MnP is determined by (i) the relative concentrations of oxidants and reductants, i.e. the cellular redox environment and (ii) MnP biodistribution. (C) 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-ND license.