Enhanced oxidative stress, resulting from imbalance between production and neutralization of ROS is a well-recognized mechanism in the pathogenesis of PDN. Recently, considerable progress has been made in the detection of diabetes-associated oxidative injury in PNS. New studies (20,21,36,41,45,81) have confirmed previously established lipid peroxidation product accumulation, GSH depletion and increase in GSSG/GSH ratio, and downregulation of superoxide dismutase (SOD) activity in the diabetic peripheral nerve. In addition, new markers of ROS-induced injury have been identified in peripheral nerve, vasa nervorum, and DRG in experimental PDN. Those include decreased catalase and total quinone reductase activities, depletion of ascorbate and taurine, and increase in dehydroascorbate/ascorbate ratio in peripheral nerve (91,92), increased production of superoxide in vasa nervorum (23), and accumulation of
8-hydroxy-2'-deoxyguanosine in DRG of STZ-diabetic rats (19). Diabetes-induced changes of the aforementioned indices were corrected by antioxidant treatment. Accumulation of nitrotyrosine (a footprint of peroxynitrite-induced protein nitration) has been documented in peripheral nerve (45), vasa nervorum (23,45), and DRG (93) in diabetic rats, and peripheral nerve of diabetic mice (92) indicating that diabetes creates not just oxidative, but oxidative-nitrosative stress in PNS. Enhanced nitrosative stress has been documented in human subjects with PDN (95).
Numerous new studies reveal the important role of oxidative stress in nerve functional, metabolic, neurotrophic, and morphological abnormalities characteristic of PDN. The role for ROS in diabetes-associated nerve conduction and blood flow deficits has been demonstrated in studies with the "universal" antioxidant DL-a-lipoic acid (5,23,91), which is known to combine free radical and metal chelating properties with an ability (after conversion to dehydrolipoic acid) to regenerate levels of other antioxidants, i.e., GSH, ascorbate, a-tocopherol, catalase, and glutathione peroxidase. It has also been confirmed with other antioxidants including the potent hydroxyl radical scavenger dimethylthiourea (96), HESD (22,23), and the SOD mimetic M40403 (97). Furthermore, diabetes-induced MNCV and SNCV deficits were reversed by the perox-ynitrite decomposition catalyst FP15 treatment (94). Two groups produced experimental evidence of an important role for oxidative stress in diabetes-associated impairment of neurotrophic support to the peripheral nerve by demonstrating that (1) diabetes and pro-oxidant treatment caused NGF and NGF-regulated neuropeptide, i.e., substance P and neuropeptide Y deficits in the sciatic nerve that were, at least partially, counteracted by a-lipoic acid (98), (2) taurine alleviated oxidative stress and prevented diabetes-induced NGF deficit in the sciatic nerve of STZ-diabetic rats (92).
Several reports suggest involvement of oxidative-nitrosative stress in the mechanisms underlying diabetic neuropathic pain and abnormal sensory responses. In the author's study (94), the tail-flick response latency was increased in diabetic NOD mice in comparison with nondiabetic mice, and this variable was normalized by short-term treatment with the peroxynitrite decomposition catalyst FP15. Studies in the "mature" short-term rat model of STZ-diabetes revealed thermal and mechanical hyperalgesia (exaggerated pain state), which was corrected by lipoic acid (99), and alleviated by the hydroxyl radical scavenger dimethylthiourea (96). The mechanisms underlying diabetes-associated tactile allodynia have not been studied in detail; however, a beneficial effect of nitecapone, an inhibitor of catechol-O-methyltransferase and antioxidant, suggests the involvement of oxidative-nitrosative stress (100).
Over past several years, the continuing debate about a "primary mechanism" of diabetic complications has centered on the origin of oxidative stress in tissue-sites for diabetic complications and its relation to other factors. According to the "unifying concept" of Brownlee derived from the studies in bovine aortic endothelial cell culture model (101,102), mitochondrial superoxide production is the primary source of oxida-tive stress in tissue-sites for diabetes complications, and this mechanism is responsible for sorbitol pathway hyperactivity, formation of AGE, and activation of PKC. Whereas the important role of mitochondria as a ROS-producing factory in diabetes is beyond doubt, this hypothesis has several major problems. First, it is unclear whether similar relations exist in other cell types, i.e., Schwann cells, and DRG neurons, and whether the mitochondrial mechanism of ROS generation is so important in high glucose-exposed human cells. Second, several extramitochondrial mechanisms have been demonstrated to be of similar, if not greater importance in endothelial cells of vasa nervorum as well as other cells. Those include xanthine oxidase, a multifunctional enzyme of an iron-sulfur molybdenum flavoprotein composition, present in high concentrations in capillary endothelial cells and producing oxygen free radicals, uric acid, and superoxide. Xanthine oxidase is increased in ischemia-reperfusion injuries, anoxia, inflammation, and diabetes mellitus (103). The importance of xanthine oxidase in PDN has been recently demonstrated by Cameron et al. (unpublished) who found a complete correction of diabetes-associated NBF and conduction deficits by the xanthine oxidase inhibitor allopurinol. The same group produced evidence suggesting that two other extramitochondrial mechanisms of ROS generation, i.e., NAD(P)H oxidase and semi-carbazide sensitive amine oxidase are also involved in the pathogenesis of PDN (104,105). A recent study (106) demonstrated the important role for NAD(P)H oxidase as well as the lipid ceramide in palmitate-induced oxidative stress in bovine retinal per-icytes, and several reports suggest the key role for NAD(P)H oxidase in the diabetic kidney (107,108). Evidence for the important contribution of other factors, i.e., 12/15-LO (109), COX-2 (110), and endothelin-1 (111), is emerging. Moreover, inhibition of Na+/H+-exchanger (NHE)-1 was found to counteract diabetes-associated superoxide generation in aorta (M.A.Yorek., unpublished). Third, the "unifying concept" is in disagreement with numerous findings supporting the role for AR in oxidative-nitrosative stress in tissue sites for diabetic complications (41,42,44,45,48) as well as in high glucose-exposed endothelial cells (43-45). Note that the role for AR in high glucose-induced superoxide production in endothelial cells has been demonstrated by several groups that used different techniques and structurally diverse ARIs (42-45). The author's group has shown that AR inhibition normalized indices of oxidative stress including lipid peroxidation product, GSH, and ascorbate concentrations as well as SOD activity and nitrotyrosine and poly(ADP-ribose) immunoreactivities in the diabetic peripheral nerve (41,45,112).
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