Diabetic neuropathy and oxidative stress

Abstract

This review will focus on the impact of hyperglycemia-induced oxidative stress in the development of diabetes-related neural dysfunction. Oxidative stress occurs when the balance between the production of reactive oxygen species (ROS) and the ability of cells or tissues to detoxify the free radicals produced during metabolic activity is tilted in the favor of the former. Although hyperglycemia plays a key role in inducing oxidative stress in the diabetic nerve, the contribution of other factors, such as endoneurial hypoxia, transition metal imbalances, and hyperlipidemia have been also suggested. The possible sources for the overproduction of ROS in diabetes are widespread and include enzymatic pathways, auto-oxidation of glucose, and mitochondrial superoxide production. Increase in oxidative stress has clearly been shown to contribute to the pathology of neural and vascular dysfunction in diabetes. Potential therapies for preventing increased oxidative stress in diabetic nerve dysfunction will be discussed.

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…Low tissue oxygen tension upregulates the expression of hypoxia-inducible factor 1-α (HIF-1α) and NF-κB 123 , a proinflammatory transcription factor that is present at high levels in peripheral nerves and dorsal root ganglia in experimental diabetic neuropathy 124 . HIF-1α causes upregulation of NADPH oxidase 2 levels 125 , a major source of ROS in vessel walls 126 . NADPH-derived superoxides react with the vasodilator nitric oxide to produce peroxynitrite 127 , which causes severe nitrosative tissue damage and inactivates tissue plasminogen activator (tPA) 128 , creating a highly prothrombotic environment.…”

Protein Mediated Oxidative Stress in Patients with Diabetes and its Associated Neuropathy: Correlation with Protein Carbonylation and Disease Activity Markers

“…Exogenous insulin and other medications are effective to control many aspects of DM and its associated complications, but still not fully defined, particularly DMN. DMN is a very common heterogeneous disorder associated with a wide range of abnormalities such as severe pain, disability and accounts for the majority of non-traumatic lower extremity deletions [4,5]. DMN may also affect sympathetic or parasympathetic function with serious consequences such as sudden cardiac death and silent myocardial ischemia [5].…”

“…Over availability of glucose promotes enhanced production of AGEs, these autooxidative glycosylation processes are probably the major cause of increased ROS and RNS production in DM patients [15][16][17]. Importantly, the formation of AGEs primarily leads biomolecular oxidation which further promotes irreversible tissue damage, including the damage of peripheral nerve and vessel wall [4,5] …”

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

“…Despite the significant pathology associated with nerve degeneration, the etiology of neuropathy is still unclear. Several pathways have been suggested to be associated with glucose neurotoxicity (Tomlinson and Gardiner 2008) and diabetic neuropathy, for example oxidative stress (Cameron et al, 1993;Coppey et al, 2001;Obrosova et al, 2005;Pop-Busui et al, 2006;Russell et al, 2002), altered polyol metabolism (Cameron and Cotter 1997), mitochondrial dysfunction (Huang et al, 2003a;Montal, 1998;Russell et al, 2002), activation of certain cysteine proteases (caspases) (Russell et al, 1999;Srinivasan et al, 2000) (Cheng and Zochodne 2003;Schmeichel et al, 2003), and regulation of growth factors and their intermediate signaling pathways (Sayers et al, 2003;Tomlinson et al, 1996). However, the role of cytokines such as transforming growth factor β (TGF-β) in development of diabetic neuropathy is not clearly defined.…”