Introduction

A. Neuropathy and Nerve Blood Flow

Neuropathy is a common complication of diabetes mellitus. Studies in patients and animal models have shown that endoneurial hypoxia, caused by impaired nerve blood flow, is a major factor in the etiology of diabetic neuropathy (l-4). Changes in vascular function, particularly of the endothelium, occur early after diabetes induction in experimental models, and in some preparations, this may even be partially mimicked by acute exposure to hyperglycemia (5,6). In streptozotocin-induced diabetic rats, sciatic nerve blood flow is reduced by approximately 50% within a week of diabetes induction (7,8), and this precedes changes in nerve conduction velocity (NCV). Large diameter sensory and motor fibers are particularly susceptible to endoneurial hypoxia in experimental diabetes (9,10).

Several treatment strategies have been used to prevent or correct the blood flow deficit in diabetic rats, and, when achieved, this results in improvements of nerve function measures, such as sensory and motor NCV, and the increased resistance to hypoxic conduction failure (3). Powerful evidence for a direct link between impaired blood flow and nerve dysfunction in diabetes comes from studies using peripheral vasodilators. These do not change the hyperglycemic state or consequent alterations in nerve metabolism such as increased polyol pathway activity; however, they can completely correct reduced NCV and attenuate the development of resistance to hypoxic conduction failure (11-15). Vasodilator treatment has also been used to improve nerve function in diabetic patients (16). Other approaches, such as chronic electrical nerve stimulation (17), and drugs that correct metabolic changes in diabetes, including L-carnitine analogues, n-6 essential fatty acids, aldose reductase inhibitors (ARIs), protein kinase C (PKC) inhibitors, antiadvanced glycation agents, and antioxidants, ameliorate NCV defects via their effects on nerve blood flow (3,18). For several of these agents, the vascular endothelium nitric oxide (NO) system appears to be a primary target because their effects on NCV and blood flow are abolished by NO synthase inhibitor cotreatment, whereas many of their other direct biochemical effects on nerve remain unchanged, for example, ARI-mediated suppression of polyol pathway metabolite levels (19-22). Several studies have identified a diminished vasa nervorum NO system in experimental diabetes (23,24). Thus, impaired nerve perfusion lies at the heart of the etiology of diabetic neuropathy. The relationship between sciatic motor NCV and nutritive (capillary) endoneurial blood flow is shown in Figure 1 for groups of diabetic rats pooled from a large number of experiments in which various doses of these drugs were used (reviewed in Refs. 3 and 4). This includes antioxidants, which are the main subject of this review. It is clear that the results of these diverse treatments all fit the same relationship: NCV increases with increasing perfusion and reaches asymptote at blood flow levels within the normal range.

B. Sources of Reactive Oxygen Species in Diabetes, NO, and Vasorelaxation

Reactive oxygen species (ROS) are increased by diabetes. NO is an important vascular target for ROS; superoxide neutralizes NO (25), and the peroxynitrite formed is a source of hydroxyl radicals that can cause endothelial damage (26). Glucose-induced oxidative stress therefore diminishes vessel endothe-lium-dependent relaxation (27), which contributes to impaired vasa nervorum function (3,4). There are several sources of ROS in diabetes, including those derived from altered metabolism such as autoxidation of glucose and its metabolites, the advanced glycation/glycoxidation process, altered prostanoid production, inefficient mitochondrial function, and upregulation of the vascular NAD(P)H oxidase system (28-30). ROS are also produced as a result of

Endoneurial Blood Flow

Figure 1 Relationship between sciatic nutritive endoneurial blood flow and motor conduction velocity in groups of streptozotocin-diabetic rats (n = 6-16) given different drug treatments in our laboratory. Diabetes duration was 1-3 months, and treatment was preventive or corrective. Groups treated with various vasodilators (*); groups treated with essential fatty acids, miscellaneous metabolically active compounds such as L-carnitine derivatives, aminoguanidine, sorbitol dehydrogenase inhibitors, PKC inhibitors, and myo-inositol (O); groups treated with different antioxidants (•); and data from aldose reductase inhibitor studies (T). The solid curve is the best-fitting Boltz-mann sigmoid curve (r = 0.95 for df = 97). The dashed rectangle denotes the non-diabetic range (± 1 SD; n = 40). All treatment effects appear to follow a similar relationship; conduction velocity is low at low flow rates and reaches an asymptote that approximates the nondiabetic level as perfusion increases.

Figure 1 Relationship between sciatic nutritive endoneurial blood flow and motor conduction velocity in groups of streptozotocin-diabetic rats (n = 6-16) given different drug treatments in our laboratory. Diabetes duration was 1-3 months, and treatment was preventive or corrective. Groups treated with various vasodilators (*); groups treated with essential fatty acids, miscellaneous metabolically active compounds such as L-carnitine derivatives, aminoguanidine, sorbitol dehydrogenase inhibitors, PKC inhibitors, and myo-inositol (O); groups treated with different antioxidants (•); and data from aldose reductase inhibitor studies (T). The solid curve is the best-fitting Boltz-mann sigmoid curve (r = 0.95 for df = 97). The dashed rectangle denotes the non-diabetic range (± 1 SD; n = 40). All treatment effects appear to follow a similar relationship; conduction velocity is low at low flow rates and reaches an asymptote that approximates the nondiabetic level as perfusion increases.

the blood flow problems they cause during episodes of ischemia-reperfusion by the xanthine oxidase mechanism (31). Another potential source that may be relevant during infection and inflammatory disease is the macrophage respiratory burst. The degree of oxidative stress seen in diabetic patients is inversely proportional to the degree of metabolic regulation (32), and very tight metabolic control is necessary to slow the development of the major diabetic complications, including neuropathy (33). Because strict glycemic control is difficult to achieve and carries with it the risk of hypoglycemic episodes, there is a strong case for supplementary treatment with antioxidants to further reduce ROS activity.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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