Therapeutic Interventions in the Glyc(oxid)ation Pathway

Author(s): Casper G. Schalkwijk.

Journal Name: Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Under Re-organization)

Volume 7 , Issue 1 , 2007

Abstract:

It is now well established that the non-enzymatic glycation can have direct and indirect biological effects leading to micro- and macrovascular complications in diabetes. Accumulation of AGEs in the extracellular matrix can cause aberrant cross-linking, resulting in vascular stiffness. AGEs can also bind to AGE-receptors, including RAGE, on different cell types resulting in cell activation. In addition, cellular formation of AGEs may be an important contributor to diabetic vascular complications by modification of growth factors. Because of these deleterious effects, a number of natural or synthetic inhibitors are currently being advanced to reduce the clinical impact of AGEs. These specific inhibitors exhibit three possible modes of action: 1. inhibition of the formation of AGEs, 2. cleavage of existing AGE cross-links, and 3. interference of the binding of AGEs to RAGE or suppression of AGE-RAGE induced signalling pathways. Aminoguanidine was the first compound designed to inhibit AGE formation and has undergone clinical trials. Due to safety concerns and lack of efficacy, aminoguanidine is unlikely to be used for therapeutic purpose. In vitro experiments and animal models have shown the potential of other agents designed to reduce the formation of AGEs such as pyridoxamine. In addition, AGE cross-link breakers such the stable derivative ALT-711 were also reported to be effective in in vitro experiments and in several diabetic animal models. Pyridoxamine and ALT-711 are now in clinical trials. The soluble form of RAGE (sRAGE) was reported to reduce deleterious effects of AGEs. Therefore, blockage of RAGE by sRAGE may be a new target for therapeutic intervention in diabetic disorders. These agents interfering in the glycation pathway offer new potential treatments for glucose-derived vascular complications of diabetes.

Keywords: AGE-receptors, glycation, Aminoguanidine, Aldose Reductase Inhibitors (ARI), Metformin, Pyridoxamine

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Article Details

VOLUME: 7
ISSUE: 1
Year: 2007
Page: [57 - 68]
Pages: 12
DOI: 10.2174/187152207779802491

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