AGE-RAGE

Diabetic Neuropathy is a comprehensible disorder, either subclinical or clinically evident that occurs in both auto-nomic and the peripheral nervous systems. The pathogenesis of diabetic peripheral neuropathy has been correlated with hyperglycaemia induced metabolic derangements and neurophysiological alterations, serum lipid changes, vascular coagulation, and thrombotic abnormalities. Neuropathic pain is a pain resulting from disease or damage of the peripheral or central nervous system and caused by primary lesion or dysfunctioning of the nerves system. Neuropathy is the most common and debilitating complication of diabetes mellitus and results in pain and de-creased motility. Long term hyperglycaemia elicits enhanced polyol pathway, increased non-enzymatic glycation of various structural proteins, which moreover increased oxidative stress as well as altered the protein kinase C (PKC) activity and poly ADP-ribose polymerase (PARP) activation that are all inter-related for the cause and de-velopment of neuropathy. These in turn activate or suppresses the protein kinase C activity or activate mitogen activated protein (MAP) kinase which furthermore resulting in functional and structural derangement of peripheral nervous system. The main aim of this review is to highlights the functioning of various mechanisms and pathways involved in the development of diabetic neuropathy.

Receptor for advanced glycation end products (RAGE) is expressed in a range of cell types such as endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. It is a multi-ligand receptor and a member of the immunoglobulin superfamily of cell surface molecules. Its repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterin and S100/calgranulins. This variety of ligands allows RAGE to be implicated in a wide spectrum of pathological conditions such as diabetes and its complications, Alzheimer’s disease, cancer and inflammation. Additionally, genetic polymorphisms in the RAGE gene may have impact on the functional activity of the receptor. 
It becomes obvious that RAGE pathway is a complicated one and the question of whether blockade of RAGE is a feasible and safe strategy for the prevention/treatment of chronic diseases is gradually gaining the attention of the pharmaceutical community.
In this review the biology of RAGE and the triggered signaling cascades involved in health and disease will be presented. Additionally, its potential as an attractive pharmacotherapeutic target will be explored by pointing out the pharmacotherapeutic agents that have been developed for RAGE blockade.