ABSTRACT
PURPOSE: The aim of this study was to investigate whether the daily administration of α-lipoic acid (LA) during 4 weeks prevents the redox disturbance in red blood cells (RBC) described in diabetes METHODS: Multiple low-dose streptozotocin (STZ) diabetes was induced in rats by the administration of 40 mg/kg STZ intraperitoneally (i.p.) for 5 consecutive days. LA was applied at a dose of 10 mg/kg i.p. for 4 weeks, starting from the last day of STZ administration. RESULTS: The LA-treated diabetic rats exhibited a general systemic improvement, revealed as the near restoration of body weight and of essential biochemical parameters. The latter was displayed as decreased hyperglycemia, lower triglyceride levels and lower serum activities of alanine aminotransferases and aspartate aminotransferases that point to a general improvement of diabetes-linked organ "lesions". The LA-treated diabetic rats also exhibited significant alleviation of oxidative stress, manifested as decreased lipid peroxidation and lower glycation levels of serum proteins and hemoglobin, while the RBC exhibited increased activities of antioxidant enzymes and elevated levels of reduced glutathione. In RBC, this was accompanied by decreased post-translational glycosylation by O-bound ß-N-acetylglucosamine (O-GlcNAc) of the antioxidant enzymes superoxide dismutase and catalase and of heat shock proteins HSP70 and HSP90. CONCLUSION: LA through its powerful antioxidant activity preserves the structural and functional integrity of RBC in diabetes. The RBC can then assume a more efficient role as the first line of systemic defense against diabetic complications arising from oxidative stress-induced damage of other tissues and organs.
Subject(s)
Acetylglucosamine/metabolism , Erythrocytes/drug effects , HSP70 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/metabolism , Thioctic Acid/pharmacology , Animals , Antioxidants/pharmacology , Catalase/metabolism , Diabetes Mellitus, Experimental/drug therapy , Electrophoresis, Polyacrylamide Gel , Erythrocytes/metabolism , Glutathione/metabolism , HSP70 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/genetics , Iron/blood , Lipid Peroxidation/drug effects , Male , Malondialdehyde/metabolism , Oxidation-Reduction , Oxidative Stress/drug effects , Rats , Rats, Wistar , Streptozocin/metabolism , Superoxide Dismutase/metabolismABSTRACT
Previously we reported that elevated circulating concentrations of the acute-phase (AP) protein α(2)-macroglobulin (α(2)M), either as typically occurring in pregnant female rats or after administration to male rats, provides radioprotection, displayed as 100% survival of experimental animals exposed to total-body irradiation with 6.7 Gy (LD(50/30)) x-rays, that is as effective as that afforded by the synthetic radioprotector amifostine. The finding that amifostine administration induces a 45-fold increase in α(2)M in the circulation led us to hypothesise that α(2)M assumes an essential role in both natural and amifostine-mediated radioprotection in the rat. In the present work we examined the activation of cytoprotective mechanisms in rat hepatocytes after the exogenous administration of α(2)M and amifostine. Our results showed that the IL6/JAK/STAT3 hepatoprotective signal pathway, described in a variety of liver-injury models, upregulated the α(2)M gene in amifostine-pretreated animals. In both α(2)M- and amifostine-pretreated rats we observed the activation of the Akt signalling pathways that mediate cellular survival. At the cellular level this was reflected as a significant reduction of irradiation-induced DNA damage that allowed for the rapid and complete restoration of liver mass and ultimately at the level of the whole organism the complete restoration of body weight. We conclude that the selective upregulation of α(2)M plays a central role in amifostine-provided radioprotection.
