Antioxidant therapy in diabetic complications: what is new?

In diabetes oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolysis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. Classic antioxidants, like vitamin E, failed to show beneficial effects on diabetic complications probably due to their only "symptomatic" action. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. Statins increase NO bioavailability and decrease superoxide production, probably interfering with NAD(P)H activity and modulating eNOS expression. ACE inhibitors and AT-1 blockers prevent hyperglycemia-derived oxidative stress modulating angiotensin action and production. This effect is of particular interest because hyperglycemia is able to directly modulate cellular angiotensin generation. Calcium channel blockers inhibit the peroxidation of cell membrane lipids and their subsequent intracellular translocation. Thiazolinediones bind and activate the nuclear peroxisome proliferator-activated receptor gamma, a nuclear receptor of ligand-dependent transcription factors. The inhibition of this receptors lead to inhibition of the inducible nitric oxide synthase and consequently reduction of peroxynitrite generation. This preventive activity against oxidative stress generation can justify a large utilization and association of this compound for preventing complications in diabetic patients, where antioxidant defences have been shown to be defective.