Thioredoxin (TRX) is a protein disulfide reductase that plays an important role in many thiol-dependent cellular reductive processes, antioxidant protection, and signal transduction. Moreover, TRX reduces and maintains the function of many proteins during oxidative stress, which is increased in diabetes. The authors recently reported that diabetes impairs brain redox status and TRX response to exercise training. As a continuation of their studies, they hypothesized that alpha-lipoic acid, a natural thiol antioxidant, has a favorable effect on the brain TRX and glutathione (GSH) system in diabetes. Streptozotocin-induced diabetes was used as a chronic model and exhaustive exercise as an acute model for disrupted redox balance. Half the diabetic and nondiabetic animals were subjected to a bout of exhaustive exercise after 8 wk with or without lipoic acid and analyzed for key thiol antioxidants. Lipoic acid neither altered diabetes-induced oxidative stress as assessed by the increased ratio of oxidized to total GSH nor had any impact on the antioxidant protein response to exercise. However, lipoic acid increased mRNA of TRX-interacting protein, an inhibitor of TRX-1, and glutaredoxin-1 in diabetes. Exercise increased TRX-1 mRNA in both diabetic and nondiabetic animals but had no effect on TRX-1 protein. Cytosolic superoxide dismutase mRNA was only increased in diabetes, whereas exercise increased the protein levels in nondiabetic animals. The findings suggest that exhaustive exercise induces mRNA of TRX-1 in the brain and that lipoic acid cannot prevent diabetes-induced disturbances in GSH homeostasis. Because lipoic acid increased TRX-interacting protein transcription in diabetes, high doses may impair TRX-1 homeostasis.
Lappalainen, Lappalainen, Laaksonen, Oksala, and Atalay are with the Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland. Khanna and Sen are with the Laboratory of Molecular Medicine, The Ohio State University Medical Center, Columbus, OH.