Inhibitors of Advanced Glycation End Product (AGE) Formation and Accumulation.

A range of chemically different compounds are known to inhibit the formation and accumulation of advanced glycation end products (AGEs) or disrupt associated signalling pathways. There is evidence that some of these agents can provide end-organ protection in chronic diseases including diabetes. Whilst this group of therapeutics are structurally and functionally different and have a range of mechanisms of action, they ultimately reduce the deleterious actions and the tissue burden of advanced glycation end products. To date it remains unclear if this is due to the reduction in tissue AGE levels per se or the modulation of downstream signal pathways. Some of these agents either stimulate antioxidant defence or reduce the formation of reactive oxygen species (ROS), modify lipid profiles and inhibit inflammation. A number of existing treatments for glucose lowering, hypertension and hyperlipidaemia are also known to reduce AGE formation as a by-product of their action. Targeted AGE formation inhibitors or AGE cross-link breakers have been developed and have shown beneficial effects in animal models of diabetic complications as well as other chronic conditions. However, only a few of these agents have progressed to clinical development. The failure of clinical translation highlights the importance of further investigation of the advanced glycation pathway, the diverse actions of agents which interfere with AGE formation, cross-linking or AGE receptor activation and their effect on the development and progression of chronic diseases including diabetic complications. Advanced glycation end products (AGEs) are (1) proteins or lipids that become glycated as a result of exposure to sugars or (2) non-proteinaceous oxidised lipids. They are implicated in ageing and the development, or worsening, of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney and Alzheimer's disease. Several antihypertensive and antidiabetic agents and statins also indirectly lower AGEs. Direct AGE inhibitors currently investigated include pyridoxamine and epalrestat, the inhibition of the formation of reactive dicarbonyls such as methylglyoxal as an important precursor of AGEs via increased activation of the detoxifying enzyme Glo-1 and inhibitors of NOX-derived ROS to reduce the AGE/RAGE signalling.