Authors: Ros, Roberto D.; Assaloni, Roberta; Ceriello, Antonio

Source: Current Drug Targets, Volume 6, Number 4, June 2005 , pp. 503-509(7)

Publisher: Bentham Science Publishers

Abstract:

In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be 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 glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications.

These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive “causal” antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionylcarnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This “causal” therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase ß isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.

Keywords: diabetic complications; oxidative stress; statins; ace inhibitors; at receptor inhibitors; calcium channel blockers; thiazolidinediones

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389450054021855

Affiliations: 1: Chair of Internal Medicine, University of Udine, P.le S. Maria della Misericordia, 33100 Udine, Italy.

Publication date: 2005-06-01

More about this publication?

• Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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