Hyperglycemia promotes production of superoxides (O^, increases flux through the Mt electron transport chain, and might be responsible for most of the key features of oxidative stress (20,23,54,55). In cell culture models of hyperglycemia, inhibition of formation prevents glucose-induced formation of advanced glycation end products (AGEs) and activation of protein kinase-C (56). O2 can also react with nitric oxide (NO) to form peroxynitrite (ONOO), which can damage intracellular lipids and proteins, resulting in lipid peroxidation, DNA fragmentation, and cell death. Accumulation of
NADH coupled with failure of the Mt creatine phosphate pump to regenerate ATP from ADP also results in disruption of the Mt electron transfer chain, and depletion of ATP (56). Depletion of ATP is associated with apoptosis in vitro (20), and similar changes are seen in chronic neuropathy in diabetic animals (57). Oxidative stress can be prevented by inhibitors of the Mt electron transport chain, for example, Mt complex II or III inhibitors, for example, TTFA or myxothiazole (20,58). Failure to prevent oxidative stress results in Mt DNA damage. DNA damage might be repaired by base excision repair, however, if not repaired there is furthermore disruption of the electron transport chain and production of further ROS. This vicious cycle of ROS production and Mt DNA damage ultimately leads to energy depletion in the cell and apoptosis (29,59).
One potential stimulus for O2 generation is NO (60). NO by interaction with the electron transport chain functions not only acts as a physiological regulator of cell respiration, but also augments the generation of ROS by Mt, and can trigger PCD (61). Evidence of increased production of reactive nitrogen species (NO and ONOO) coupled with evidence of PCD implicate nitrosative injury in models of diabetic neuropathy (62,63). NO is formed by activation of NO synthase (NOS), which analyzes the oxidation of L-arginine to NO and citrulline (for review see ref. 64). Neuronal NOS is the primary constitutively active isoform in neurons. NO is relatively unstable in vivo, however, it can bind thiol-containing proteins, thereby substantially increasing its halflife. This process, called S-nitrosylation results in directed and rapid activation or deac-tivation of proteins and affects the signaling of specific proteins (64-67).
NO might have both neuroprotective and neurotoxic roles depending on other modifying pathways. NO induced toxicity depends in general on the degree of local generation of NO and/or O2 (68,69). ONOO- can inactivate electron transfer complexes I, II, and ATPase (70), reversibly nitroslylate or irreversibly nitrate critical proteins and enzymes, including manganese superoxide dismutase, cytochrome-c, aconitase, and VDAC (reviewed in refs. 64,71). In combination, these effects of NO increase oxidative stress and nitrosative stress through the overproduction of S-nitrosylated proteins (72). Manganese superoxide dismutase, a superoxide scavenger, might protect from ONOO-induced cell death (69).
Activation of neuronal NOS, endothelial NOS, or the inducible form of NOS might produce paradoxical responses in the peripheral nerve. Inducible NOS is increased in the arteries of diabetic rats (73), but unchanged in DRG neurons from chronically diabetic rats (74). Deficits in endothelial NO and other endothelial vasodilators can result in reduced nerve perfusion and function (64,75,76). With ischemia, there is failure of the endothelial NOS:NO axis that will result in reduced perfusion of the peripheral nerve and further aggravate ischemic oxidative injury to the peripheral nerve.
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