Authors: Sugimoto, Kazuhiro; Yasujima, Minoru; Yagihashi, Soroku

Source: Current Pharmaceutical Design, Volume 14, Number 10, April 2008 , pp. 953-961(9)

Publisher: Bentham Science Publishers

Abstract:

Diabetic neuropathy is the commonest form of peripheral neuropathy in the developed countries of the world. In diabetic patients, the presence of peripheral neuropathy increases their risks for developing foot ulceration and subsequent necrosis that necessitates lower limb amputation. Although the precise mechanisms underlying diabetic neuropathy remain unclear, there is evidence that hyperglycemia- induced formation of advanced glycation end products (AGEs) is related to diabetic neuropathy; AGE-modified peripheral nerve myelin is susceptible to phagocytosis by macrophages and contributes to segmental demyelination; modification of major axonal cytoskeletal proteins such as tubulin, neurofilament, and actin by AGEs results in axonal atrophy/degeneration and impaired axonal transport; and glycation of extracellular matrix protein laminin leads to impaired regenerative activity in diabetic neuropathy. Recently, the receptor for AGEs (RAGE) has been found to colocalize with AGEs in diabetic peripheral nerves. This suggests that, in diabetic neuropathy, AGEs and AGE/RAGE interactions induce oxidative stress, result in upregulation of nuclear factor (NF)-kappaB and various NF-kappaB-mediated proinflammatory genes, and exaggerate neurological dysfunction, including altered pain sensation. Additionally, AGE/RAGE-induced oxidative stress further accelerates formation of glycoxidation products such as Nepsilon-(carboxymethyl)lysine and pentosidine. Although new drugs that inhibit the formation of AGEs and block the AGE-RAGE interaction are being studied, no effective treatment modalities against AGE-induced nerve injury are currently available clinically. A therapeutic strategy to prevent and ameliorate diabetic neuropathy using anti-AGE agents needs to be established. In this review, the current issues involved in the role of the glycation process and the potential treatment options for diabetic neuropathy are explored.

Keywords: Diabetic neuropathy; AGEs; oxidative stress; RAGE; CML

Document Type: Research article

DOI: http://dx.doi.org/10.2174/138161208784139774

Affiliations: 1: Department of Laboratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho,Hirosaki, 036-8562, Japan.

Publication date: 2008-04-01

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  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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