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Oxidative Stress in the Pathogenesis of Diabetic Neuropathy

Department of Neurology (A.M.V., J.W.R., E.L.F.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Neurology (P.L.), Mayo Clinic, Rochester, Minnesota 55905

Correspondence: Address all correspondence and requests for reprints to: Andrea M. Vincent, Ph.D., Department of Neurology, University of Michigan, Room 4414, Kresge III, 200 Zina Pitcher Place, Ann Arbor, Michigan 48109. E-mail: andreav{at}umich.edu

	Abstract

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
Oxidative stress results from a cell or tissue failing to detoxify the free radicals that are produced during metabolic activity. Diabetes is characterized by chronic hyperglycemia that produces dysregulation of cellular metabolism. This review explores the concept that diabetes overloads glucose metabolic pathways, resulting in excess free radical production and oxidative stress. Evidence is presented to support the idea that both chronic and acute hyperglycemia cause oxidative stress in the peripheral nervous system that can promote the development of diabetic neuropathy. Proteins that are damaged by oxidative stress have decreased biological activity leading to loss of energy metabolism, cell signaling, transport, and, ultimately, to cell death. Examination of the data from animal and cell culture models of diabetes, as well as clinical trials of antioxidants, strongly implicates hyperglycemia-induced oxidative stress in diabetic neuropathy. We conclude that striving for superior antioxidative therapies remains essential for the prevention of neuropathy in diabetic patients.

I. Introduction

II. The Chemistry of Oxidative Stress

A. O₂^–.

B. Hydrogen peroxide (H₂O₂)

C. Nitric oxide (NO)

III. Cellular Injury through Excess ROS Production

IV. Cellular Antioxidant Defense

A. Dietary antioxidants

B. GSH

C. Trx

D. Antioxidant enzymes

V. Production of ROS in Diabetes

A. Advanced glycosylated end product (AGE)-mediated ROS formation

B. The polyol pathway

C. Protein kinase C (PKC) activation

D. MAPK activities

E. ROS formation at the mitochondria

VI. Neuronal Response to Oxidative Stress

VII. Biomarkers of Oxidative Stress

A. Antioxidant reserves

B. Antioxidant enzymes

C. Free radical generation

D. Protein, lipid, and DNA adducts

VIII. Antioxidant Therapy for Diabetes Complications

A. Aldose reductase inhibitors

B. Nerve growth factor (NGF)

IX. Clinical Trials of Antioxidant Therapy in Diabetes Complications

A. -Lipoic acid

B. Vitamins E and C

C. The future of antioxidant therapy in clinical trials

X. Summary

	I. Introduction

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
OXIDATIVE STRESS OCCURS in a cellular system when the production of free radical moieties exceeds the antioxidant capacity of that system. If cellular antioxidants do not remove free radicals, radicals attack and damage proteins, lipids, and nucleic acids. The oxidized or nitrosylated products of free radical attack have decreased biological activity, leading to loss of energy metabolism, cell signaling, transport, and other major functions. These altered products also are targeted for proteosome degradation, further decreasing cellular function. Accumulation of such injury ultimately leads a cell to die through necrotic or apoptotic mechanisms.

Chronic hyperglycemia causes oxidative stress in tissues prone to complications in patients with diabetes (1, 2). Diabetes is an epidemic in developed countries. In the United States, 16 million individuals are diabetic, and the number is increasing at a rate of 5% per year. The major form of diabetes in the population is type 2, which accounts for up to 95% of diabetes cases in the United States (3). Among children, type 1 diabetes poses a greater risk, although this may change in the future because the rate of type 2 diabetes in children and adolescents is increasing (4). The microvascular complications of diabetes carry a high morbidity and, when coupled with macrovascular complications, high mortality (5). The most common microvascular complication is neuropathy. Although exact prevalence depends on the diagnostic criteria used to identify neuropathy, most studies suggest that 50% of patients with a 20-yr history of diabetes, of both type 1 and type 2, have neuropathy (6, 7). Around 10% of these cases of neuropathy are associated with abnormal sensations and pain (8). The incidence of neuropathy increases with duration of diabetes and is accelerated by poor control (9).

The majority of work to date has focused upon the peripheral nervous system, and so, unless stated otherwise, comments in this review refer to the peripheral nervous system. One should note, however, that deficits in the central nervous system are recognized as a feature of diabetes. Generally, spinal cord lesions are considered a rare event in diabetes, although a recent study demonstrated overall slowing of spinal cord potentials in a population of patients with type 2 diabetes at 5–10 yr after disease onset (10). Studies in diabetic rats suggest that the same signal transduction pathways that are implicated in peripheral neuropathy in the dorsal root ganglia are also affected in the brain (11). Again, attempts to unify the mechanisms that ultimately produce neuronal degeneration point to at least a component of oxidative stress. Mild cognitive dysfunction is not uncommon in adults with type 1 diabetes through a mechanism that appears to be linked to the development of vascular complications (12). Similarly, in patients that have Alzheimer’s disease, development of type 2 diabetes with vascular complications accelerates the brain deposition of amyloid protein and neurofibrillar tangles (13).

The mechanisms underlying oxidative stress in chronic hyperglycemia and the development of neuropathy have been examined in animal models (14). This oxidative stress is associated with the development of apoptosis in neurons and supporting glial cells and so could be the unifying mechanism that leads to nervous system damage in diabetes (15, 16). This review explores the evidence for oxidative stress as a significant mediator in the development of diabetic neuropathy as well as the potential for prevention of complications through rigorous antioxidant therapy.

Although this review is mainly focused upon the loss of neuronal function and survival as a cause of diabetic neuropathy, it is important to consider other mechanisms that contribute to the disorder. Neurons not only are lost in diabetes, but their ability to regenerate is also impaired, particularly the small-caliber nerve fibers (17). In patients with diabetic neuropathy, both degeneration and regeneration are present simultaneously, suggesting that the disorder is highly dynamic (7). Over time, the balance between degeneration and regeneration shifts toward more degeneration, and the aim of therapeutic regimens should be to restore the balance on the side of regeneration. The inability to regenerate nerve fibers is related to the degree of neuropathy, suggesting that therapeutic interventions to improve regeneration will be more effective at early stages of disease (17). The mechanisms leading to loss of regeneration may include impaired insulin action (18), loss of growth factor systems (19), and decrease in specific isoforms of protein kinase C (20). Schwann cells are important in the regenerative process, and these also can be impaired in diabetes through hyperglycemia, hypoxia, and oxidative stress (reviewed in Ref.21). Understanding and the ability to intervene in oxidative stress, therefore, may both prevent neuron degeneration and promote regeneration (7).

	II. The Chemistry of Oxidative Stress

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
Several free radical species are normally produced in the body to perform specific functions. Superoxide (O₂^–.), hydrogen peroxide (H₂O₂), and nitric oxide (NO) are three free radical reactive oxygen species (ROS) that are essential for normal physiology, but are also believed to accelerate the process of aging and to mediate cellular degeneration in disease states. These agents together produce highly active singlet oxygen, hydroxyl radicals, and peroxynitrite that can attack proteins, lipids, and DNA. Figure 1 illustrates the different forms of ROS as well as showing examples of their formation and removal within cells. These reactions are described in more detail below.

View larger version (21K): [in this window] [in a new window]   FIG. 1. The charged states of oxygen and the formation and detoxification of oxygen radicals in cells. On the left, the various oxidative states of the molecule are illustrated to assist the reader in understanding the terminology of free radicals. As molecular oxygen participates in biochemical reactions in the cell, electrons are shuttled between molecules, and highly reactive intermediates are produced and then removed through the activities of specific enzymes. These reactions are summarized in the schematic on the right.

O₂^–. overproduction occurs in complication-prone tissues when cellular metabolism is perturbed by excess glucose. ATP synthase is inhibited, and electron transfer slows. This can cause overproduction of O₂^–. in two ways. First, the half-life of highly reactive quinone intermediates is prolonged, increasing the release of electrons to combine with molecular oxygen and form O₂^–.. Second, when electron transfer no longer can regenerate NAD⁺, the enzyme NADH oxidase is activated and generates O₂^–. as a byproduct (Fig. 2).

B. Hydrogen peroxide (H₂O₂)
H₂O₂ is produced after the spontaneous or SOD-catalyzed dismutation of O₂^–. as well as many other enzymatic reactions. Unlike O₂^–., which remains at the site of production, H₂O₂ can diffuse across membranes and through the cytosol (29). This ROS is another component of leukocyte-mediated defense against bacteria. Because H₂O₂ is a powerful oxidizing agent, cells express abundant catalase, glutathione (GSH), and thioredoxin (Trx) that convert H₂O₂ to water. When H₂O₂ reacts with free Fe²⁺, the iron is oxidized and hydroxyl radicals are produced. There are many severe consequences of hydroxyl radical production, including loss of vasodilation that can lead to endothelial injury and tissue hypoxia (30).

C. Nitric oxide (NO)
NO is generated through the activity of a cytosolic enzyme known as NO synthase (NOS). There are both constitutively expressed, calcium-dependent isoforms of NOS and an inducible isoform that is associated with inflammation and cell activation (31, 32). NO plays a major role in regulating vascular tone by activating soluble guanylate cyclases that regulate ion channels. In addition, NO modulates cellular respiration through direct inhibition of cytochrome oxidase by competitively occupying the oxygen-binding site (33). The inducible form of NOS is increased in the arteries of diabetic rats (34). Damaged neurons recover more slowly in the presence of NO, and conversely, NOS inhibitors promote neuronal recovery from injury (35). NO is also believed to act as a neurotransmitter (36). The dual role of NO as both beneficial and detrimental is illustrated in stroke models. Under ischemic insult, endothelial NO produces vasodilation that can improve blood flow, but neuronal NO is produced downstream of calcium dysregulation and can prevent energy generation in the mitochondria (37). More importantly, NO acts as an antioxidant in certain environments and prevents lipid peroxidation (38). However, when O₂^–. increases, NO reacts with the O₂^–. to form peroxynitrite and becomes a prooxidant.

	III. Cellular Injury through Excess ROS Production

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
The production of ROS is under tight control in healthy cells, but overproduction during metabolic dysfunction leads to cellular injury. Although both O₂^–. and NO are relatively inert, when they combine they form the highly reactive peroxynitrite that attacks and inhibits proteins and lipids. In addition, both O₂^–. and NO can attack iron-sulfur centers of enzymes and other proteins to release iron atoms and consequently inhibit enzyme/protein activities. There are many important proteins that are exquisitely sensitive to this type of inhibition including complexes I–III of the electron transfer chain, aconitase of the trichloroacetic acid cycle, and biotin synthase (39, 40).

The formation of lipid, protein, and nucleic acid adducts involves a complex chain reaction using a range of biological substrates that contain reactive methylene groups. Intermediates in the chain reaction can have extremely high oxidative ability and so cellular damage can be extensive. The chemistry of these reactions has been reviewed previously (41, 42). Lipids present in plasma, mitochondrial, and endoplasmic reticulum membranes are major targets of ROS attack and peroxidation. End products of lipid peroxidation, known as lipid peroxides, can be toxic to a cell and require removal by GSH as described below. Similarly, proteins and nucleic acids can be subject to peroxidation and nitrosylation. Although these end products are not usually directly toxic to the cell, accumulation of inactive proteins can overload the ability of a cell to recycle them, and damage of DNA is known to activate the mechanisms of apoptosis. In addition, accumulation of modified proteins decreases their function, leading to severe loss of normal activity. Axonal transport can be slowed, leading to decreased delivery of growth factors and intermediates from the synapse to the cell body and resulting in induction of apoptosis (43). Oxidative modification of transcription factors not only leads to decreased expression of many proteins such as apoptosis inhibitory factor, complex I, and Bcl-2, but also results in increased expression of stress proteins that may be proapoptotic, including cyclooxygenase 2, poly-ADP ribose polymerase, and Jun kinase (JNK) (44, 45, 46, 47).

Production of ROS in all cells not only results in deleterious events but also can play a role in differentiation and development. Redox status can have profound effects on gene expression, so that oxidative stress increases growth factors, stress response elements, and apoptosis pathways (48). In contrast, certain proteins including cytokines, cytochrome c oxidase, and enzymes involved in glucose respiration are repressed by oxidative stress signaling (49). Understanding of gene regulation by reactive oxygen intermediates is rapidly expanding. Once the mechanisms are more fully understood, the ability of a cell to respond to stress by changing gene expression may provide an important therapeutic target.

The most significant consequence of oxidative stress in dividing cells may be DNA modifications that produce genomic instability and mutations (50). Nondividing neurons may suffer less from oxidative damage of DNA. Yet, mitochondrial DNA is particularly sensitive to oxidative damage (51), which would impair energy regulation and thus would be critically important in high energy-requiring neurons. Oxidative stress-mediated neuronal degeneration is implicated in several types of neurodegenerative disease (52, 53, 54). In nondividing cells like neurons, damage to proteins and lipids may be more injurious than DNA damage, because this may render proteins unable to perform axonal transport and signaling (43). For example, synaptosomal membranes as well as cytosolic proteins become oxidized, and these changes can be correlated to alterations in brain function (55). Loss of function in neurons rapidly promotes necrotic or apoptotic mechanisms (53, 56).

	IV. Cellular Antioxidant Defense

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
Antioxidants are defined as any compound that can donate at least one hydrogen atom to a free radical, resulting in the termination of radical chain reactions. An alternative type of antioxidant is defined by its ability to prevent the initiation of a free radical chain reaction rather than to terminate them. This latter type of antioxidant is usually dependent upon the ability to bind metal ions and includes ceruloplasmin, transferrin, and albumin (57). Cells must maintain the levels of antioxidants, often defined as antioxidant potential, through dietary uptake or de novo synthesis. Excess production of free radicals can deplete the intracellular antioxidants, resulting in oxidative stress. Even brief, acute hyperglycemic episodes such as an oral glucose tolerance test or a meal can decrease the antioxidant capacity of plasma in both normal and diabetic subjects and increase oxidative stress in diabetic patients (58, 59). As a type 2 diabetic patient ages, increased basal levels of free radical production and decreased antioxidants are even further exacerbated by elevated plasma glucose (60). Analysis of individual vitamin and enzyme components of the antioxidant system in man reveals significant changes in diabetes (61). Vitamins A and E and catalase are decreased in both type 1 and 2 patients compared with controls. Whereas GSH-metabolizing enzymes are decreased in type 1 but not type 2 patients, SOD activity is lower in type 2 but not type 1. These changes do not correlate with observed complications (61).

A. Dietary antioxidants
Water-soluble vitamin C and fat-soluble vitamin E together make up an antioxidant system for mammalian cells. Vitamin C, or ascorbic acid, is considered the most important antioxidant in plasma and forms the first line of defense against plasma lipid peroxidation (62). Vitamin E is the generic description for all tocopherol and tocotrienol derivatives that comprise the major lipophilic antioxidant of exogenous origin in tissues (63). Comparison of the isoforms of tocopherol including DL--tocopherol, mixed tocopherols (containing R,R,R--, R,R,R-ß-, R,R,R--, and R,R,R--tocopherol, D-tocopherols, and tocopherol excipient) and Ronoxan MAP demonstrates no significant difference in antioxidant capacity although the antioxidant activity of -tocopherol acetate is completely lost (63). Different properties of the isoforms have been identified, however. Tocotrienol, but not tocopherol, inhibits angiogenesis of tumors and is recommended as a dietary supplement to decrease tumorigenesis (64). Tocotrienol directly regulates the activity of 12-lipoxygenase that may mediate neuronal excitotoxicity, and so this compound possesses an additional neuroprotective capacity distinct from antioxidant action (65).

Interestingly, for the purposes of considering antioxidant therapy against oxidative stress, antioxidants may act synergistically. In particular, ascorbate regenerates -tocopherol from the tocopherol radical to reduce the toxicity of tocopherol intermediates (66). Dietary supply of these vitamins leads to a rapid increase in concentration in plasma and cells and a measurable increase in antioxidant potential (67, 68). The use of vitamin supplements for prevention of diabetic neuropathy will be discussed later in Section IX.

B. GSH
GSH is by far the most important antioxidant in most mammalian cells. This ubiquitous tripeptide, -Glu-Cys-Gly, performs many cellular functions. In particular, the thiol-containing moiety is a potent reducing agent. GSH is maintained at a concentration of 0.2–10 mM in all mammalian cells (69). Many cells can synthesize GSH de novo by -glutamylcysteine synthetase first forming a -peptide bond between one cysteine and one glutamate residue. Next, glycine is added by GSH synthetase. Neurons do not contain the -glutamylcysteine synthetase enzyme and so require the dipeptide to be secreted from glial cells (70, 71).

The most significant role of GSH is as a water-soluble antioxidant. Toxic lipid peroxides combine with two molecules of GSH under the control of GSH peroxidase to form an inert lipid hydroxyl group, GSH disulfide (GSSG), and water. In addition, GSH is involved in amino acid transport, deoxyribonucleotide synthesis, maintenance of functionally important protein thiol groups in reduced form, and conjugation with toxic compounds such as xenobiotics under the control of glutathione-S-transferase to promote their elimination from the cell (72, 73). After participation in redox reactions, GSH is regenerated from GSSG by the enzyme GSSG reductase using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor.

Depletion of GSH in the cell renders it susceptible to oxidative injury (74). The agent 3-hydroxy-4-pentenoate specifically depletes mitochondrial GSH and enhances cell death induced by prooxidants such as tert-butyl hydroperoxide (75). In contrast, loading the cell, and particularly the mitochondria, with GSH can prevent neuronal apoptosis produced by ischemia (76) and excitotoxicity (77). Overexpression of glutathione-S-transferase in neuroblastoma cells increases their resistance to oxidative stress (78).

C. Trx
Another small protein antioxidant within cells that can maintain redox homeostasis is Trx. Similar to GSH, Trx is regenerated by a NADPH-dependent reductase. In contrast to the critical role GSH plays in chemical detoxification, Trx is essential for maintenance of normal protein structure. Although there is some redundancy between these small molecules, Trx has a more significant role in regulation of catalytic activity, protein-protein interactions, trafficking, activation, degradation, and transcription factors binding to DNA (79). The concentrations of Trx are maintained in the micromolar range in mammalian cells. Mitochondria express distinct isoforms of Trx reductase and Trx synthetase; overexpression of these isoforms confers resistance to prooxidant stress (79).

Additional enzymes that catalyze the reduction of hydrogen peroxide or alkyl peroxide to water, or the corresponding alcohol, are the peroxiredoxins. Detailed analysis of their sequences indicates that these enzymes possess a Trx-like fold and consequently are homologs of both Trx peroxidase and GSH peroxidase (80). There are at least six isoforms of the peroxiredoxin family that are differentially expressed in mammalian tissues (81). These enzymes are rapidly induced after oxidative stress and form part of the early stress response (82).

D. Antioxidant enzymes
In addition to the enzymes that synthesize and maintain antioxidant molecules such as GSH, specific antioxidant enzymes are expressed that detoxify free radical entities in cells, tissues, and extracellular fluids. One of the most ubiquitous of these is SOD. The three major isoforms of SOD are: cytosolic CuZn-SOD (SOD1), mitochondrial SOD (SOD2), and extracellular SOD. Extracellular SOD is similar in structure to SOD1 but is localized in the extracellular space. SOD converts O₂^–. to H₂O₂ and oxygen. Decreased expression of SOD2 leads to decreased mitochondrial GSH and increased oxidative stress (83). Complete knockout of SOD2 is lethal within days of birth due to renal dysfunction (84).

Additional enzymes are present, each with specific ROS targets. Catalase is a cytosolic enzyme that converts H₂O₂ to water, and therefore its activity needs to be present when SOD is active. Myeloperoxidase is a peroxisomal enzyme that accelerates the conversion of H₂O₂ to highly reactive singlet oxygen as part of cellular antibacterial function (85). This enzyme activity is necessarily regulated through both sequestration in the peroxisome and by chaperones, but is rapidly translocated and activated after exposure to inflammatory mediators.

	V. Production of ROS in Diabetes

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
One unifying mechanism of nervous system injury in diabetes lies in the ability of both metabolic and vascular insults to increase cellular oxidative stress and impair the function of mitochondria (16, 86). Recent studies have supported this hypothesis, including in vivo and in vitro measurement of oxidative stress in sensory neurons as well as neuronal protection by antioxidants. In vitro, application of 10–20 mM glucose to dorsal root ganglia neurons leads to production of O₂^–. and H₂O₂ that leads to lipid oxidation and neuronal death. This glucose-induced death is prevented by IGF-I, in part through decreased ROS production (15). Further evidence comes from feeding mice with a high-glucose diet. In this case, the mice experience hyperglycemia that leads to free radical production and oxidative stress (87).

There is a close correlation between oxidative stress in diabetes and the development of complications. In type 1 diabetic patients, oxidative stress is evident within a few years of diagnosis before the onset of complications. As the disease progresses, antioxidant potential decreases, and plasma lipid peroxidation products increase depending upon the level of glycemic control (88). Type 2 diabetic patients have increased lipid peroxidation compared with age-matched control subjects, as well as decreased plasma GSH and GSH-metabolizing enzymes and antioxidant potential, all of which relate directly to the rate of development of complications (89, 90, 91). Similarly, oxidative stress is linked to preclinical features of disease, such as vascular endothelial activation that can lead to atherosclerosis (92). The early increase of oxidative stress in diabetes is more pronounced in women and may account for increased cardiovascular disease in female patients (93).

Figure 2 outlines the potential mechanisms underlying the production of excess ROS in the nervous system by high glucose. Each of the potential pathways is discussed below. A recent review on vascular cell biochemistry outlines similar pathways as instrumental in mediating glucose-mediated endothelial damage (94).

View larger version (37K): [in this window] [in a new window]   FIG. 2. Hyperglycemia activates many signaling mechanisms in cells. Four major pathways that can lead to cell injury downstream of hyperglycemia are illustrated. 1) Excess glucose shunts to the polyol pathway that depletes cytosolic NADPH and subsequently GSH. 2) Excess glucose also undergoes autooxidation to produce AGEs that impair protein function and also activate RAGEs that use ROS as second messengers. 3) PKC activation both further increases hyperglycemia and also exacerbates tissue hypoxia. 4) Overload and slowing of the electron transfer chain leads to escape of reactive intermediates to produce O2–. as well as activation of NADH oxidase that also produces O2–.. A unifying mechanism of injury in each case is the production of ROS that impair protein and gene function. TCA, Trichloroacetic acid; PAI-1, plasminogen activator inhibitor-1. [Reproduced with permission from E. L. Feldman: J Clin Invest 111:431–433, 2003 (206 ).]

AGEs bind to a cell surface receptor known as receptor for AGE (RAGE), a multiligand member of the Ig superfamily. This binding initiates a cascade of signal transduction events involving p44/p42 MAPKs, nuclear factor-B, p21Ras, and other intermediates (98, 99). Interaction of AGEs with RAGE induces the production of ROS through a mechanism that involves localization of prooxidant molecules at the cell surface (100) and a key role for activated NADPH oxidase (101). In neuronal cell lines, application of AGEs depletes GSH, but this is prevented in the presence of antioxidants (102). Antioxidants or antibodies against RAGE prevent both oxidative stress and the downstream signaling pathways that can be activated by ligation of RAGE. AGE-mediated ROS production is particularly implicated in blood vessel endothelial activation and diabetic vascular complications (103, 104).

B. The polyol pathway
The enzyme aldose reductase converts toxic aldehydes to inactive alcohols (2). Glucose is a poor substrate for aldose reductase, but at high concentrations this enzyme converts glucose to sorbitol, initiating the polyol pathway of glucose conversion to fructose. Similar to GSH reductase, the enzyme aldose reductase is dependent upon NADPH as a cofactor. Therefore, excessive activation of the polyol pathway depletes cytosolic NADPH and subsequently depletes GSH, leaving the cell vulnerable to free radicals produced during normal cellular functions such as electron transfer. In addition, accumulation of sorbitol produces a cellular osmotic stress that also generates oxidative stress (105). This pathway has been a target for therapies against diabetes complications including neuropathy (106). Recent human genetic and biochemical data link polymorphisms of the aldose reductase gene to increased risk of diabetic complications, with the principal allele associated with increased disease risk causing a 2- to 3-fold increase in aldose reductase gene expression (106).

C. Protein kinase C (PKC) activation
The activation of the PKC pathway in hyperglycemia is included here for completeness, although the contribution to diabetic neuropathy is likely to occur through its effects in vascular blood flow and microvascular disease rather than directly in neuronal cells. PKC has several unique structural features that facilitate its regulation according to redox status. Prooxidants react with the regulatory domain to stimulate PKC activity, but antioxidants react with the catalytic domain of PKC and inhibit its activity (107). Activity of PKC is increased in the retina, kidney, and microvasculature of diabetic rats, but there is no evidence for altered activity of any of the PKC isoforms in the peripheral neurons (108, 109). This suggests that the lipolytic pathway and production of diacylglycerol are the main causes of PKC activation in nonneuronal cell types (110). Once activated, PKC activates the MAPKs that phosphorylate transcription factors and thus alter the balance of gene expression (111). Specifically, it is the stress genes such as heat shock proteins and c-Jun kinases that increase after PKC activation and can lead to apoptosis or vascular atherosclerosis. A role for PKC in inducing neuronal degeneration possibly at the level of the endothelial cell is implicated by three studies. Inhibition of PKCß reduces oxidative stress and normalizes blood flow and nerve conduction deficits in diabetic rats (110, 112). High glucose causes nuclear factor-B activation in endothelial cells, leading to ROS formation, and cellular activation, an effect that is prevented in the presence of a PKC inhibitor (113).

D. MAPK activities
All three classes of the MAPK, ERK1/2, JNK, and p38, are activated in the dorsal root ganglia of diabetic rats. The significance of these signaling pathways in the development of diabetic neuropathy is not clear. Treatment with antioxidants decreases the activation of ERKs, but increases JNK, which may suggest that the ERKs are injurious and JNK is protective (111). Yet, persistent activation of JNK is normally associated with injury (114). Peroxynitrite-induced oxidative stress activates p38 in neuroblastoma cells, and this leads to growth arrest and apoptosis (115). At present, the studies of MAPK involvement in neuropathy are mainly descriptive, and mechanistic studies are required to clarify the role of these signaling pathways.

E. ROS formation at the mitochondria
As mentioned earlier, O₂^–. is a normal by-product of metabolic processes; therefore, when glycolysis, electron transfer, and oxidative phosphorylation are chronically or acutely overloaded, excess O₂^–. produces oxidative stress. The importance of these mechanisms in producing hyperglycemic neuronal degeneration is highlighted in recent studies of uncoupling proteins. Uncoupling proteins are a family of proton carriers that are expressed at the inner mitochondrial membrane and are responsible for proton leak across the membrane into the cristae. Thus, these protons that were pumped into the intermembrane space through electron transfer bypass oxidative phosphorylation, and these two processes are said to be uncoupled. Activity of uncoupling proteins, therefore, decreases the inner mitochondrial membrane potential and can relieve the stress of excess NADH entering the electron transfer chain (116). Overexpression of uncoupling proteins in cultured dorsal root ganglia neurons significantly decreases both basal and hyperglycemia-induced ROS formation and prevents glucose-induced neuronal death (117). Interestingly, O₂^–. can mediate the activation of mitochondrial uncoupling proteins in skeletal muscle cells, demonstrating that this may be an innate mechanism for protection against excess activity-induced O₂^–. in muscle cell mitochondria (118).

Oxidative stress in the mitochondria critically alters energy regulation and survival through at least three mechanisms. First, physiological levels of NO reversibly compete with molecular oxygen for binding to cytochrome c oxidase, producing reversible inhibition and acting as a regulatory switch for electron transfer. In contrast, in the presence of excess O₂^–., NO is converted to ONOO^.–, which competes with molecular oxygen for irreversible binding to cytochrome c oxidase. Thus, ONOO^.– profoundly affects mitochondrial function and inhibits ATP synthesis (33, 119). Second, mitochondrial oxidative stress through excess O₂^–. and ONOO^.– production inhibits the import of essential proteins to the mitochondria that are in turn degraded in the cytosol (120). Finally, oxidative damage of existing inner membrane proteins induces membrane permeability transition, a permeabilization of the mitochondrial inner membrane that precedes cytochrome c release and apoptosis (121).

The mitochondrial mechanisms of ROS production and neuronal injury are activated within 1–2 h of hyperglycemic insult and so may be the greatest contributor to diabetic neuropathy (A. M. Vincent, L. L. McLean, C. Backus, and E. L. Feldman, unpublished data). Many diabetic patients with good overall glucose control still experience neuropathy, so brief postprandial periods of hyperglycemia that produce ROS but no significant AGE formation or polyol pathway activation may be sufficient to injure neurons. Supporting evidence for this conclusion is obtained in patients with impaired glucose tolerance. Many patients with impaired glucose tolerance have significant peripheral neuropathy, and in some cases painful neuropathy is the presenting symptom (17). We would infer that neuropathy in these cases is most likely attributable to brief postprandial hyperglycemic episodes. This suggests that the ability to prevent ROS formation in the presence of short hyperglycemic episodes could, at least partially, block the development of diabetic neuropathy.

	VI. Neuronal Response to Oxidative Stress

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
The antioxidant defense system of a cell is clearly not static but can respond to environmental changes. In culture, vascular endothelial cells up-regulate SOD, GSH peroxidase, and catalase through increased gene expression over a period of 3–10 d (122). Because glucose enters neurons via facilitated concentration-dependent transport, neurons are likely more susceptible to glucose flux and subsequent increased oxidative stress. However, a study in 3- and 12-month streptozotocin-treated rats with nerve conduction deficits did not show changes in antioxidant enzymes except for increased catalase at 12 months (123). The changes in antioxidant enzymes and antioxidant reserves in diabetes are discussed under individual sections in Section VII.

	VII. Biomarkers of Oxidative Stress

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
Measuring biomarkers of oxidative stress is an essential step toward better understanding the pathogenesis and developing treatments for diabetic neuropathy. There are several approaches that may be adopted, including measurements of the depletion of antioxidant reserves, changes in the activities of antioxidant enzymes, free radical production, and presence of protein, lipid, and DNA free radical adducts. For the purposes of clinical assessment, measurements of end products of free radical attack may be the most reliable determination of the occurrence of oxidative stress because enzyme activities and cellular antioxidants are likely to display transient changes. Yet, the other measures also have utility depending on the nature of the study.

The presence of oxidative stress in biological fluids can be simply assessed by examination of spontaneous visible luminescence. This phenomenon is the result of oxidized biomolecules with long half-life luminescent intermediates (124). Measures of spontaneous luminescence were increased in the urine of patients with known oxidative stress such as hyperthyroid and muscular dystrophy patients or smokers compared with healthy controls (125). At present, this method is not routinely used in diabetes studies, because more specific end points are selected.

A. Antioxidant reserves
Several assays are available for the measurement of total antioxidant potential in clinical samples, including tissue, plasma, and urine. The relative merits of these assay techniques are reviewed elsewhere (126, 127, 128). The total radical antioxidant potential assay clearly demonstrates that diabetic patients have lower antioxidant defenses and that total antioxidant potential is a better indication of antioxidant status than examination of individual antioxidants (129). Measures of individual antioxidants often do not correlate with glucose levels (88). In both clinical diabetes and experimental in vivo and in vitro models, antioxidant potential correlates with the degree of glycemic control and decreases with prolonged diabetes (130, 131). This loss of antioxidant potential is exemplified by demonstrations that the antioxidant ß-amino acid taurine is depleted in sciatic nerve after 6 wk of diabetes in rats (132). Dietary supplementation with antioxidants increases the total radical antioxidant potential measures in diabetic patients (133). Acute hyperglycemia in type 2 diabetes increases plasma 8-isoprostanes without necessarily changing overall antioxidant potential, suggesting that short episodes of hyperglycemia are more closely linked to free radical-mediated oxidative damage than prolonged fasting hyperglycemia (134).

B. Antioxidant enzymes
The enzymes responsible for detoxifying free radicals or regenerating antioxidant molecules can provide an indication of the level of stress experienced in a cell or tissue. These enzymes are usually measured by in vitro activity assays, although changes in transcription can also provide evidence of cell stress. In long-term diabetes, catalase, GSH reductase, GSH peroxidase, and SOD decrease in complication-prone tissue (135). One study reports elevated CuZn-SOD activity in the blood, although the increased activity did not correct the deficiency of antioxidant capacity or hyperglycemia-induced lipid peroxidation (136). The study suggested that treatment with oral antidiabetic drugs was responsible for decreases in GSH peroxidase and catalase below control levels. In a cell culture model of peripheral neuron hyperglycemia, there is an initial increase in catalase and SOD as the neurons attempt to respond to oxidative stress (A. M. Vincent, L. L. McLean, C. Backus, and E. L. Feldman, unpublished studies). Initiation of apoptosis, however, occurs within 3–6 h, after which the antioxidant enzymes rapidly decrease. Different models of diabetes have produced conflicting data regarding increases or decreases in antioxidant enzymes. In cultured vascular endothelial cells, glucose-induced oxidative stress leads to increased mRNA for antioxidant enzymes for a period of 2 wk (122). NADH oxidase is activated in the brain and kidney of diabetic rats but decreased in the liver (137). Because the purpose of this enzyme is to regenerate NAD⁺ from NADH to maintain redox status, this finding strongly suggests that oxidative stress is occurring in the non-insulin-dependent neurons and kidney cells.

C. Free radical generation
Measurement of free radicals is difficult in animal models or clinical samples because of their transient nature. Hyperglycemia is closely associated with production of O₂^–. and peroxides in cell culture models (104). In these models, the use of fluorescent probes can lead to reliable and reproducible measures of oxidative stress in real time. These cell-permeable probes, which are retained in the cell following the cleavage of an ester conjugate, increase fluorescence at a specific wavelength after oxidation by free radical attack (138, 139).

D. Protein, lipid, and DNA adducts
As already stated, the end products of free radical attack are reliable and relatively straightforward indicators of oxidative stress. These modified cell components may be measured by several different techniques, including HPLC, gas chromatography-mass spectroscopy, Western blotting, and ELISA. Biopsy can be used for analysis of oxidized biomolecules in tissues that are particularly at risk from diabetic complications. These analyses can be performed not only on tissue but also on plasma and urine. Urine analysis can reveal nitrosylated proteins (140), lipid oxidation products such as 8-isoprostanes (141), and the DNA adduct 8-hydroxy-2-deoxyguanosine (8-OH-2dG) (142). These three indicators, along with other lipid adducts, i.e., malondialdehyde and 4-hydroxynonenyl and carbonyl derivatives of protein side chains, constitute the most common markers of oxidative stress in biological systems.

Generally, measures of antioxidants or oxidized end products are more consistently performed in plasma than urine (143). The excretion of 8-OH-2dG in urine may be misleading, because this parameter is more strongly influenced by the degree of oxygen consumption and activity of xenobiotic-metabolizing enzymes (144). Blood cell 8-OH-2dG is increased in both type 1 and type 2 diabetic patients (145). Nitrotyrosine increases and antioxidant status decreases to similar extents in diabetic patients with or without complications, but oxidized proteins are significantly higher in diabetic patients with complications than in those without any complications (146). This suggests that NO initiation of nitrosylation of proteins may be less significant in producing complications than other free radicals. Nitration of proteins can lead to rapid proteasomal degradation (147); therefore, they can be removed from the cell and resynthesized. Carbonylated proteins and peptides are also inactivated by oxidative stress (148). Measurements of protein carbonyls are highly sensitive, and they can be detected in the plasma of both type 1 and type 2 diabetic patients even without complications (149, 150).

	VIII. Antioxidant Therapy for Diabetes Complications

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
Ten years ago, the Diabetes Control and Complications Trial demonstrated that good glycemic control is the most effective means of decreasing diabetes complications in type 1 patients (2, 151). In another study, uncontrolled diabetes led to pronounced oxidative stress that was reversed when patients attained glycemic control through treatment with glibenclamide or glicaxide (152). Nonetheless, continual tight control is still a challenge in most cases. Therefore, additional therapies that target the pathways leading to hyperglycemia-induced complications are crucial for maintaining long-term quality of life for diabetes patients. Given the hypothesis that oxidative stress may mediate vascular, microvascular, and specific tissue complications in diabetes, antioxidant therapy remains a vital therapy that needs to be exploited. In addition to antioxidants, aldose reductase inhibitors and growth factor therapies also may provide protection through reduction of oxidative stress.

A. Aldose reductase inhibitors
As stated earlier, hyperglycemia-mediated activation of the polyol pathway can produce oxidative stress that may partially underlie diabetes complications. Aldose reductase inhibitors have been tested in experimental diabetic neuropathy, primarily in the streptozotocin rat (153). The aldose reductase inhibitor sorbinil corrects the early deficits in peripheral nerve function with concomitant decreases in parameters of oxidative stress (154). Similarly, the aldose reductase inhibitor WAY-121509 corrects sciatic nerve conduction velocity and endoneurial blood flow and tissue sorbitol accumulation (155). Clinical trials of aldose reductase inhibitors have mostly been disappointing, with a lack of efficacy and unacceptable side effects (6). Zenarestat (Fujisawa Pharmaceutical Company, Ltd., Osaka, Japan) is one drug that was effective in type 1 (156) and type 2 (157) diabetic animals. In a phase II clinical trial, zenarestat produced greater than 80% sorbitol suppression and improved nerve conduction velocity slowing and small-nerve fiber density in a 52-wk trial (158). However, a larger phase III trial was suspended because of renal function disorders. The potent aldose reductase inhibitor fidarestat (Sanwa Kagaku KenKyusho, Nagoya, Japan) remains in clinical trial, as current studies are showing therapeutic benefit both in streptozotocin rats (159) and in diabetic patients (160, 161).

B. Nerve growth factor (NGF)
The justification for, and outcomes of, clinical trials using NGF have been reviewed elsewhere (162). The discovery of neurotrophic factors such as NGF raised the hope that these agents could be used clinically to combat neurodegenerative disease. Recent in vitro studies demonstrated that NGF can prevent neuronal oxidative stress by increasing intracellular concentrations of GSH (163), suggesting that altering cellular redox potential may be an important function of NGF. NGF also inhibits the up-regulation of NOS in injured neurons (164). Early clinical trials were promising in patients with diabetic neuropathy, but later phase III trials failed, probably because of poor experimental design (162).

	IX. Clinical Trials of Antioxidant Therapy in Diabetes Complications

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
The strongest indicators for the role for oxidative stress in diabetic neuropathy are the trials of antioxidants in both animal models and patients. Animal models of diabetes have limitations including a short life span compared with possibly decades of disease progression in human patients (165). These data require careful analysis, because each therapeutic agent may have effects outside of regulation of antioxidant activity. For example, administration of the antioxidants vitamin C or -lipoic acid, as well as free amino acids, also improves responses to insulin and thus can provide additional benefit to the proposed reduction of oxidative stress in tissues (166, 167, 168, 169). Vitamin E decreases blood glucose in type 1 diabetic rats through an unknown mechanism (170). Following a discussion of more prominent antioxidants, a number of other agents that have been tested in animal models and/or the diabetes clinic are summarized in Table 1.

A. -Lipoic acid

-Lipoic acid is licensed for use in diabetic patients in Germany. Cross-sectional studies continue to demonstrate that supplementation with -lipoic acid significantly improves antioxidant defense and decreases oxidative stress even in patients with poor glycemic control (180). German trials also suggest that treatment with -lipoic acid improves the microcirculation, suggesting protective effects other than, or in addition to, decreasing cellular oxidative stress (181). Larger multicenter randomized double-blind placebo trials in Europe and North America have demonstrated limited effects on neuropathic symptoms and electrophysiological testing but suggest that longer-term assessment of neuropathic deficits is merited (182, 183). Slight improvements in cardiac autonomic neuropathy were demonstrated in the DEKAN study (184), and the drug was safe and well tolerated. A recent phase III clinical trial, the SYDNEY trial, demonstrated that iv administration of -lipoic acid rapidly and significantly improves several neuropathic symptoms and nerve function in patients with stage 2 diabetic sensorimotor polyneuropathy (185). This is strong support for the use of antioxidants in the treatment of diabetic neuropathy, and the use of oral -lipoic acid is currently in a phase III clinical trial in the United States.

B. Vitamins E and C
As a critical antioxidant for the protection of plasma lipids, vitamin C will require supplementation under conditions of prolonged or repeated prooxidant conditions such as hyperglycemia (62). Chronic administration of 1 g/d vitamin C in aged type 2 diabetic patients decreases plasma free radicals and increases cellular GSH levels over a period of 4 months (186). Vitamin C supplementation alone shows limited therapeutic benefit in type 1 diabetes (187) and is more commonly used in combination with vitamin E or other agents. Uses of vitamin C in combination therapies are discussed below.

Vitamin E has been more broadly examined in diabetes models. Interestingly, the incorporation of vitamin E into erythrocyte membranes is impaired in the hyperglycemic state; therefore, decreased antioxidant defense may be further exacerbated in poorly controlled diabetes (188). Rat models of diabetes show some therapeutic benefit in the presence of vitamin E therapy. Diabetes-induced susceptibility to low-density lipoprotein peroxidation is prevented in the presence of vitamin E (189). Dietary vitamin E supplementation also improves fatty acid metabolism and decreases lipid peroxidation in tissues of diabetic rats (190) and improves blood flow and nerve morphometric parameters in the heart (191). In diabetic rats, vitamin E supplementation prevents reactive astrocytosis in the brain that is associated with lipid peroxidation (192). Diabetes-induced changes in antioxidant enzymes in different organs are corrected to differing extents by vitamin E, but the combination of vitamin E with another antioxidant, stobadine, provides superior protection against deficits in these enzymes (193).

In healthy human subjects, -tocopherol decreases evidence of oxidative stress through low-density lipoprotein oxidizability and presence of urinary F₂-isoprostane (67). In this regard, -lipoic acid may be slightly more potent than -tocopherol in decreasing the same oxidative stress parameters, and there is no added benefit in combining the two agents (67). Small clinical studies demonstrate improvements in a variety of oxidative stress parameters in diabetic patients receiving antioxidant vitamin supplements. Combined oral vitamin C and E therapy reduces oxidative stress in the eye (68) and improves vascular endothelial function in type 1, but not type 2, diabetes (194). Plasma low-density lipoprotein oxidation is decreased after treatment with high doses (1632 mg/d) of vitamin E (195). Topical application of vitamin E improves skin microcirculation and evidence of ROS in type 2 diabetics (196). Finally, urinary 8-isoprostane F2 and 11-dehydro-thromboxane B2 were decreased after treatment with 600 mg/d vitamin E in a population of 85 diabetic patients (197). Direct correlations between improved antioxidant status and the incidence of neuropathy have not yet been made.

Despite many positive clinical trials using vitamin E, some conflicting data exist for diabetes as well as other disorders such as cancer and cardiovascular disease (198, 199). Therefore, broad recommendations for the use of vitamin E and other dietary supplements have not been established. One caution for the preventive intake of -tocopherol is the evidence that supplementation with -tocopherol produces deleterious changes in the bioavailability of - and -tocopherol. The different isoforms have different properties, such as in vascular disease and antiproliferative effects, and so additional research into the dietary application of vitamin E isoforms is warranted (200, 201).

C. The future of antioxidant therapy in clinical trials
The clinical trials to date have provided strong evidence that oxidative stress is a critical mediator of diabetes complications including neuropathy. To improve future clinical trials, previous studies should be closely examined. High doses of single-antioxidant supplements may perturb the antioxidant-prooxidant balance of cell systems (200, 202). Therefore, mixtures of antioxidant therapies, possibly in combination with trace elements and vitamins that enhance metabolic processes, may provide a better therapeutic option. Monitoring of patients’ antioxidant reserves also may identify development of deficits that could be ameliorated by altering the therapeutic antioxidant regimen. Earlier discussions in this review suggest that GSH may be the most important tissue antioxidant. Therapies aimed at increasing cellular GSH could target the GSH-synthesizing enzymes as well as dietary increases of cysteine or its precursor 2-oxothiazolidine-4-carboxylate, as cysteine is the rate-limiting substrate for GSH synthase (203). GSH is not taken up well by cells, but an esterified form is, and this directly increases the levels of GSH in tissues, plasma, and cerebrospinal fluid (69). Another review of the literature regarding the use of botanicals and dietary supplements in diabetic peripheral neuropathy concludes that evening primrose oil, -lipoic acid, and capsaicin have been most widely used, but that their efficacy is not yet established (204).

	X. Summary

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 
Diabetic neuropathy probably arises from a combination of microvascular and neuronal deficits. Oxidative stress can contribute significantly to these deficits and may be a direct result of hyperglycemia. Brief postprandial peaks in plasma glucose are sufficient to generate hyperglycemic oxidative stress. In contrast, acute glucose deprivation also causes apoptosis of peripheral neurons through a mechanism that at least partially involves oxidative stress (205). Therefore, until we can fully control blood glucose levels, therapies such as antioxidants that are targeted against oxidative stress remain our most promising approach to preventing neuropathy as well as other complications in diabetes.

	Acknowledgments

 
We thank Dr. Eric Schwab, Dr. Tracy Schwab, and Ms. Lisa McLean for assistance with literature searching and assimilation. We also thank Ms. Judy Boldt for excellent secretarial support.

	Footnotes

 
This work was supported by the following grants and institutions: Juvenile Diabetes Research Foundation (JDRF) Center for the Study of Complications in Diabetes (to A.M.V., J.W.R., and E.L.F.); National Institutes of Health (NIH) Grant NS42056; the Office of Research Development (Medical Research Service), Department of Veterans Affairs (to J.W.R.); NIH Grants NS2 2352 and NS3 9722, JDRF Grant 1-2001-554, and Mayo Foundation Funds (to P.L.); and NIH Grants NS38849 and NS36778 and the Program for Understanding Neurological Diseases (to E.L.F.).

Abbreviations: AGE, Advanced glycosylation end product; GSH, glutathione; GSSG, GSH disulfide; H₂O₂, hydrogen peroxide; JNK, Janus kinase; NAD⁺, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NGF, nerve growth factor; NO, nitric oxide; NOS, NO synthase; O₂^–., superoxide; 8-OH-2dG, 8-hydroxy-2-deoxyguanosine; PKC, protein kinase C; RAGE, receptor for AGE; ROS, reactive oxygen species; SOD, superoxide dismutase; Trx, thioredoxin.

	References

Top Abstract I. Introduction II. The Chemistry of... III. Cellular Injury through... IV. Cellular Antioxidant Defense V. Production of ROS... VI. Neuronal Response to... VII. Biomarkers of Oxidative... VIII. Antioxidant Therapy for... IX. Clinical Trials of... X. Summary References

 

1. Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L 2001 The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab Res Rev 17:189–212[CrossRef][Medline]
2. Greene DA, Sima AA, Stevens MJ, Feldman EL, Lattimer SA 1992 Complications: neuropathy, pathogenetic considerations. Diabetes Care 15:1902–1925[Abstract]
3. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF 2003 Lifetime risk for diabetes mellitus in the United States. JAMA 290:1884–1890[Abstract/Free Full Text]
4. Fagot-Campagna A, Pettitt DJ, Engelgau MM, Burrows NR, Geiss LS, Valdez R, Beckles GL, Saaddine J, Gregg EW, Williamson DF, Narayan KM 2000 Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr 136:664–672[CrossRef][Medline]
5. Windebank AJ, Feldman EL 2001 Diabetes and the nervous system. In: Aminoff MJ, ed. Neurology and general medicine. London: Churchill Livingstone; 341–364
6. Feldman EL, Stevens MJ, Russell JW, Greene DA 2001 Diabetic neuropathy. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. Baltimore: Lippincott Williams & Wilkins; 1391–1399
7. Apfel SC 1999 Nerve regeneration in diabetic neuropathy. Diabetes Obes Metab 1:3–11[CrossRef][Medline]
8. Calcutt NA 2002 Potential mechanisms of neuropathic pain in diabetes. Int Rev Neurobiol 50:205–228[Medline]
9. Feldman EL, Stevens MJ, Russell JW 2002 Diabetic peripheral and autonomic neuropathy. In: Sperling MA, ed. Contemporary endocrinology. Totowa, NJ: Humana Press; 437–461
10. Varsik P, Kucera P, Buranova D, Balaz M 2001 Is the spinal cord lesion rare in diabetes mellitus? Somatosensory evoked potentials and central conduction time in diabetes mellitus. Med Sci Monit 7:712–715[Medline]
11. Bhardwaj SK, Sandhu SK, Sharma P, Kaur G 1999 Impact of diabetes on CNS: role of signal transduction cascade. Brain Res Bull 49:155–162[CrossRef][Medline]
12. Ryan CM, Geckle MO, Orchard TJ 2003 Cognitive efficiency declines over time in adults with type 1 diabetes: effects of micro- and macrovascular complications. Diabetologia 46:940–948[CrossRef][Medline]
13. Messier C 2003 Diabetes, Alzheimer’s disease and apolipoprotein genotype. Exp Gerontol 38:941–946[CrossRef][Medline]
14. Schmeichel AM, Schmelzer JD, Low PA 2003 Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. Diabetes 52:165–171[Abstract/Free Full Text]
15. Russell JW, Sullivan KA, Windebank AJ, Herrmann DN, Feldman EL 1999 Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis 6:347–363[CrossRef][Medline]
16. Russell JW, Golovoy D, Vincent AM, Mahendru P, Olzmann JA, Mentzer A, Feldman EL 2002 High glucose induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 16:1738–1748[Abstract/Free Full Text]
17. Polydefkis M, Griffin JW, McArthur J 2003 New insights into diabetic polyneuropathy. JAMA 290:1371–1376[Abstract/Free Full Text]
18. Pierson CR, Zhang W, Sima AA 2003 Proinsulin C-peptide replacement in type 1 diabetic BB/Wor-rats prevents deficits in nerve fiber regeneration. J Neuropathol Exp Neurol 62:765–779[Medline]
19. Chiarelli F, Santilli F, Mohn A 2000 Role of growth factors in the development of diabetic complications. Horm Res 53:53–67[Medline]
20. Sakaue Y, Sanada M, Sasaki T, Kashiwagi A, Yasuda H 2003 Amelioration of retarded neurite outgrowth of dorsal root ganglion neurons by overexpression of PKC in diabetic rats. Neuroreport 14:431–436[CrossRef][Medline]
21. Eckersley L 2002 Role of the Schwann cell in diabetic neuropathy. Int Rev Neurobiol 50:293–321[Medline]
22. Fridovich I 1995 Superoxide radical and superoxide dismutases. Annu Rev Biochem 64:97–112[CrossRef][Medline]
23. Uemura S, Matsushita H, Li W, Glassford AJ, Asagami T, Lee KH, Harrison DG, Tsao PS 2001 Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress. Circ Res 88:1291–1298[Abstract/Free Full Text]
24. Burdon RH 1995 Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 18:775–794[CrossRef][Medline]
25. Khodr B, Khalil Z 2001 Modulation of inflammation by reactive oxygen species: implications for aging and tissue repair. Free Radic Biol Med 30:1–8[CrossRef][Medline]
26. Lee MH, Hyun DH, Jenner P, Halliwell B 2001 Effect of proteasome inhibition on cellular oxidative damage, antioxidant defences and nitric oxide production. J Neurochem 78:32–41[CrossRef][Medline]
27. Vazifeh D, Abdelghaffar H, Labro MT 2002 Effect of telithromycin (HMR 3647) on polymorphonuclear neutrophil killing of Staphylococcus aureus in comparison with roxithromycin. Antimicrob Agents Chemother 46:1364–1374[Abstract/Free Full Text]
28. Sawa A 2001 Alteration of gene expression in Down’s syndrome (DS) brains: its significance in neurodegeneration. J Neural Transm Suppl 361–371
29. Antunes F, Cadenas E 2000 Estimation of H₂O₂ gradients across biomembranes. FEBS Lett 475:121–126[CrossRef][Medline]
30. Pieper GM, Langenstroer P, Gross GJ 1993 Hydroxyl radicals mediate injury to endothelium-dependent relaxation in diabetic rat. Mol Cell Biochem 122:139–145[CrossRef][Medline]
31. Roth S 1997 Role of nitric oxide in retinal cell death. Clin Neurosci 4:216–223[Medline]
32. Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS 2002 Role of nitric oxide in inflammation-mediated neurodegeneration. Ann NY Acad Sci 962:318–331[CrossRef][Medline]
33. Ghafourifar P, Bringold U, Klein SD, Richter C 2001 Mitochondrial nitric oxide synthase, oxidative stress and apoptosis. Biol Signals Recept 10:57–65[CrossRef][Medline]
34. Bardell AL, Macleod KM 2001 Evidence for inducible nitric-oxide synthase expression and activity in vascular smooth muscle of streptozotocin-diabetic rats. J Pharmacol Exp Ther 296:252–259[Abstract/Free Full Text]
35. Suzuki T, Tatsuoka H, Chiba T, Sekikawa T, Nemoto T, Moriya H, Sakuraba S, Nakaya H 2001 Beneficial effects of nitric oxide synthase inhibition on the recovery of neurological function after spinal cord injury in rats. Naunyn Schmiedebergs Arch Pharmacol 363:94–100[CrossRef][Medline]
36. Bruhwyler J, Chleide E, Liegeois JF, Carreer F 1993 Nitric oxide: a new messenger in the brain. Neurosci Biobehav Rev 17:373–384[CrossRef][Medline]
37. Huang PL, Lo EH 1998 Genetic analysis of NOS isoforms using nNOS and eNOS knockout animals. Prog Brain Res 118:13–25[Medline]
38. Violi F, Marino R, Milite MT, Loffredo L 1999 Nitric oxide and its role in lipid peroxidation. Diabetes Metab Res Rev 15:283–288[CrossRef][Medline]
39. Brown GC, Borutaite V 1999 Nitric oxide, cytochrome c and mitochondria. Biochem Soc Symp 66:17–25[Medline]
40. Andersson U, Leighton B, Young ME, Blomstrand E, Newsholme EA 1998 Inactivation of aconitase and oxoglutarate dehydrogenase in skeletal muscle in vitro by superoxide anions and/or nitric oxide. Biochem Biophys Res Commun 249:512–516[CrossRef][Medline]
41. Beckman KB, Ames BN 1999 Endogenous oxidative damage of mtDNA. Mutat Res 424:51–58[Medline]
42. Requena JR, Fu MX, Ahmed MU, Jenkins AJ, Lyons TJ, Thorpe SR 1996 Lipoxidation products as biomarkers of oxidative damage to proteins during lipid peroxidation reactions. Nephrol Dial Transplant 11(Suppl 5):48–53
43. Metodiewa D, Koska C 2000 Reactive oxygen species and reactive nitrogen species: relevance to cyto(neuro)toxic events and neurologic disorders. An overview. Neurotox Res 1:197–233[Medline]
44. De La Monte SM, Ganju N, Feroz N, Luong T, Banerjee K, Cannon J, Wands JR 2000 Oxygen free radical injury is sufficient to cause some Alzheimer-type molecular abnormalities in human CNS neuronal cells. J Alzheimers Dis 2:261–281[Medline]
45. Conn KJ, Ullman MD, Eisenhauer PB, Fine RE, Wells JM 2001 Decreased expression of the NADH:ubiquinone oxidoreductase (complex I) subunit 4 in 1-methyl-4-phenylpyridinium-treated human neuroblastoma SH-SY5Y cells. Neurosci Lett 306:145–148[CrossRef][Medline]
46. Paschen W, Mengesdorf T, Althausen S, Hotop S 2001 Peroxidative stress selectively down-regulates the neuronal stress response activated under conditions of endoplasmic reticulum dysfunction. J Neurochem 76:1916–1924[CrossRef][Medline]
47. Pugazhenthi S, Nesterova A, Jambal P, Audesirk G, Kern M, Cabell L, Eves E, Rosner MR, Boxer LM, Reusch JE 2003 Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons. J Neurochem 84:982–996[CrossRef][Medline]
48. Allen RG, Tresini M 2000 Oxidative stress and gene regulation. Free Radic Biol Med 28:463–499[CrossRef][Medline]
49. Morel Y, Barouki R 1999 Repression of gene expression by oxidative stress. Biochem J 342:481–496
50. Bohr VA, Dianov GL 1999 Oxidative DNA damage processing in nuclear and mitochondrial DNA. Biochimie 81:155–160[Medline]
51. Nagley P, Zhang C, Lim ML, Merhi M, Needham BE, Khalil Z 2001 Mitochondrial DNA deletions parallel age-linked decline in rat sensory nerve function. Neurobiol Aging 22:635–643[CrossRef][Medline]
52. Kikuchi H, Furuta A, Nishioka K, Suzuki SO, Nakabeppu Y, Iwaki T 2002 Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis. Acta Neuropathol (Berl) 103:408–414[CrossRef][Medline]
53. Deng G, Su JH, Ivins KJ, Van Houten B, Cotman CW 1999 Bcl-2 facilitates recovery from DNA damage after oxidative stress. Exp Neurol 159:309–318[CrossRef][Medline]
54. Ozawa T, Hayakawa M, Katsumata K, Yoneda M, Ikebe S, Mizuno Y 1997 Fragile mitochondrial DNA: the missing link in the apoptotic neuronal cell death in Parkinson’s disease. Biochem Biophys Res Commun 235:158–161[CrossRef][Medline]
55. Butterfield DA, Koppal T, Howard B, Subramaniam R, Hall N, Hensley K, Yatin S, Allen K, Aksenov M, Aksenova M, Carney J 1998 Structural and functional changes in proteins induced by free radical-mediated oxidative stress and protective action of the antioxidants N-tert-butyl--phenylnitrone and vitamin E. Ann NY Acad Sci 854:448–462[CrossRef][Medline]
56. Aksenova MV, Aksenov MY, Payne RM, Trojanowski JQ, Schmidt ML, Carney JM, Butterfield DA, Markesbery WR 1999 Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal lobe in different neurodegenerative disorders. Dement Geriatr Cogn Disord 10:158–165[CrossRef][Medline]
57. Stocks J, Gutteridge JM, Sharp RJ, Dormandy TL 1974 The inhibition of lipid autoxidation by human serum and its relation to serum proteins and -tocopherol. Clin Sci Mol Med 47:223–233[Medline]
58. Ceriello A, Bortolotti N, Crescentini A, Motz E, Lizzio S, Russo A, Ezsol Z, Tonutti L, Taboga C 1998 Antioxidant defences are reduced during the oral glucose tolerance test in normal and non-insulin-dependent diabetic subjects. Eur J Clin Invest 28:329–333[CrossRef][Medline]
59. Ceriello A, Bortolotti N, Motz E, Pieri C, Marra M, Tonutti L, Lizzio S, Feletto F, Catone B, Taboga C 1999 Meal-induced oxidative stress and low-density lipoprotein oxidation in diabetes: the possible role of hyperglycemia. Metabolism 48:1503–1508[CrossRef][Medline]
60. Tessier D, Khalil A, Fulop T 1999 Effects of an oral glucose challenge on free radicals/antioxidants balance in an older population with type II diabetes. J Gerontol A Biol Sci Med Sci 54:M541–M545
61. Merzouk S, Hichami A, Madani S, Merzouk H, Berrouiguet AY, Prost J, Moutairou K, Chabane-Sari N, Khan NA 2003 Antioxidant status and levels of different vitamins determined by high performance liquid chromatography in diabetic subjects with multiple complications. Gen Physiol Biophys 22:15–27[Medline]
62. Frei B, Stocker R, England L, Ames BN 1990 Ascorbate: the most effective antioxidant in human blood plasma. Adv Exp Med Biol 264:155–163[Medline]
63. Di Mambro VM, Azzolini AE, Valim YM, Fonseca MJ 2003 Comparison of antioxidant activities of tocopherols alone and in pharmaceutical formulations. Int J Pharm 262:93–99[CrossRef][Medline]
64. Inokuchi H, Hirokane H, Tsuzuki T, Nakagawa K, Igarashi M, Miyazawa T 2003 Anti-angiogenic activity of tocotrienol. Biosci Biotechnol Biochem 67:1623–1627[CrossRef][Medline]
65. Khanna S, Roy S, Ryu H, Bahadduri P, Swaan PW, Ratan RR, Sen CK 2003 Molecular basis of vitamin E action. Tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. J Biol Chem 278:43508–43515[Abstract/Free Full Text]
66. Mukai K, Nishimura M, Kikuchi S 1991 Stopped-flow investigation of the reaction of vitamin C with tocopheroxyl radical in aqueous triton X-100 micellar solutions. The structure-activity relationship of the regeneration reaction of tocopherol by vitamin C. J Biol Chem 266:274–278[Abstract/Free Full Text]
67. Marangon K, Devaraj S, Tirosh O, Packer L, Jialal I 1999 Comparison of the effect of -lipoic acid and -tocopherol supplementation on measures of oxidative stress. Free Radic Biol Med 27:1114–1121[CrossRef][Medline]
68. Peponis V, Papathanasiou M, Kapranou A, Magkou C, Tyligada A, Melidonis A, Drosos T, Sitaras NM 2002 Protective role of oral antioxidant supplementation in ocular surface of diabetic patients. Br J Ophthalmol 86:1369–1373[Abstract/Free Full Text]
69. Anderson ME 1998 Glutathione: an overview of biosynthesis and modulation. Chem Biol Interact 111–112:1–14
70. Iwata-Ichikawa E, Kondo Y, Miyazaki I, Asanuma M, Ogawa N 1999 Glial cells protect neurons against oxidative stress via transcriptional up-regulation of the glutathione synthesis. J Neurochem 72:2334–2344[CrossRef][Medline]
71. Keelan J, Allen NJ, Antcliffe D, Pal S, Duchen MR 2001 Quantitative imaging of glutathione in hippocampal neurons and glia in culture using monochlorobimane. J Neurosci Res 66:873–884[CrossRef][Medline]
72. Lowndes HE, Beiswanger CM, Philbert MA, Reuhl KR 1994 Substrates for neural metabolism of xenobiotics in adult and developing brain. Neurotoxicology 15:61–73[Medline]
73. Hayes JD, McLellan LI 1999 Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic Res 31:273–300[Medline]
74. Rizzardini M, Lupi M, Bernasconi S, Mangolini A, Cantoni L 2003 Mitochondrial dysfunction and death in motor neurons exposed to the glutathione-depleting agent ethacrynic acid. J Neurol Sci 207:51–58[CrossRef][Medline]
75. Shan X, Jones DP, Hashmi M, Anders MW 1993 Selective depletion of mitochondrial glutathione concentrations by (R,S)-3-hydroxy-4-pentenoate potentiates oxidative cell death. Chem Res Toxicol 6:75–81[CrossRef][Medline]
76. Li L, Shen YM, Yang XS, Wu WL, Wang BG, Chen ZH, Hao XJ 2002 Effects of spiramine T on antioxidant enzymatic activities and nitric oxide production in cerebral ischemia-reperfusion gerbils. Brain Res 944:205–209[CrossRef][Medline]
77. Kobayashi MS, Han D, Packer L 2000 Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity. Free Radic Res 32:115–124[CrossRef][Medline]
78. Xie C, Lovell MA, Xiong S, Kindy MS, Guo J, Xie J, Amaranth V, Montine TJ, Markesbery WR 2001 Expression of glutathione-S-transferase isozyme in the SY5Y neuroblastoma cell line increases resistance to oxidative stress. Free Radic Biol Med 31:73–81[CrossRef][Medline]
79. Chen Y, Cai J, Murphy TJ, Jones DP 2002 Overexpressed human mitochondrial thioredoxin confers resistance to oxidant-induced apoptosis in human osteosarcoma cells. J Biol Chem 277:33242–33248[Abstract/Free Full Text]
80. Schroder E, Ponting CP 1998 Evidence that peroxiredoxins are novel members of the thioredoxin fold superfamily. Protein Sci 7:2465–2468[Medline]
81. Rhee SG, Kang SW, Chang TS, Jeong W, Kim K 2001 Peroxiredoxin, a novel family of peroxidases. IUBMB Life 52:35–41[Medline]
82. Bast A, Wolf G, Oberbaumer I, Walther R 2002 Oxidative and nitrosative stress induces peroxiredoxins in pancreatic ß cells. Diabetologia 45:867–876[CrossRef][Medline]
83. Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardson A 1998 Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 273:28510–28515[Abstract/Free Full Text]
84. Lebovitz RM, Zhang H, Vogel H, Cartwright J, Dionne L, Lu N, Huang S, Matzuk MM 1996 Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci USA 93:9782–9787[Abstract/Free Full Text]
85. Weiss SJ, LoBuglio AF, Kessler HB 1980 Oxidative mechanisms of monocyte-mediated cytotoxicity. Proc Natl Acad Sci USA 77:584–587[Abstract/Free Full Text]
86. Vinik AI 1999 Diabetic neuropathy: pathogenesis and therapy. Am J Med 107:17S–26S
87. Folmer V, Soares JC, Rocha JB 2002 Oxidative stress in mice is dependent on the free glucose content of the diet. Int J Biochem Cell Biol 34:1279–1285[CrossRef][Medline]
88. Tsai EC, Hirsch IB, Brunzell JD, Chait A 1994 Reduced plasma peroxyl radical trapping capacity and increased susceptibility of LDL to oxidation in poorly controlled IDDM. Diabetes 43:1010–1014[Abstract]
89. Altomare E, Vendemiale G, Chicco D, Procacci V, Cirelli F 1992 Increased lipid peroxidation in type 2 poorly controlled diabetic patients. Diabete Metab 18:264–271[Medline]
90. Zaltzberg H, Kanter Y, Aviram M, Levy Y 1999 Increased plasma oxidizability and decreased erythrocyte and plasma antioxidative capacity in patients with NIDDM. Isr Med Assoc J 1:228–231[Medline]
91. Sundaram RK, Bhaskar A, Vijayalingam S, Viswanathan M, Mohan R, Shanmugasundaram KR 1996 Antioxidant status and lipid peroxidation in type II diabetes mellitus with and without complications. Clin Sci (Lond) 90:255–260[Medline]
92. Elhadd TA, Kennedy G, Hill A, McLaren M, Newton RW, Greene SA, Belch JJ 1999 Abnormal markers of endothelial cell activation and oxidative stress in children, adolescents and young adults with type 1 diabetes with no clinical vascular disease. Diabetes Metab Res Rev 15:405–411[CrossRef][Medline]
93. Marra G, Cotroneo P, Pitocco D, Manto A, Di Leo MA, Ruotolo V, Caputo S, Giardina B, Ghirlanda G, Santini SA 2002 Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated type 1 diabetes: a case for gender difference. Diabetes Care 25:370–375[Abstract/Free Full Text]
94. Brownlee M 2001 Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820[CrossRef][Medline]
95. Thornalley PJ 2002 Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options. Int Rev Neurobiol 50:37–57[Medline]
96. Cameron NE, Cotter MA 1995 Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents. J Clin Invest 96:1159–1163[Medline]
97. Singh R, Barden A, Mori T, Beilin L 2001 Advanced glycation end-products: a review. Diabetologia 44:129–146[CrossRef][Medline]
98. Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM 1997 Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272:17810–17814[Abstract/Free Full Text]
99. Wautier JL, Wautier MP, Schmidt AM, Anderson GM, Hori O, Zoukourian C, Capron L, Chappey O, Yan SD, Brett J 1994 Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc Natl Acad Sci USA 91:7742–7746[Abstract/Free Full Text]
100. Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, Pinsky D, Stern D 1994 Enhanced cellular oxidant stress by the interaction of advanced glycation endproducts with their receptors/binding proteins. J Biol Chem 269:9889–9897[Abstract/Free Full Text]
101. Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL 2001 Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol 280:E685–E694
102. Deuther-Conrad W, Loske C, Schinzel R, Dringen R, Riederer P, Munch G 2001 Advanced glycation endproducts change glutathione redox status in SH-SY5Y human neuroblastoma cells by a hydrogen peroxide dependent mechanism. Neurosci Lett 312:29–32[CrossRef][Medline]
103. Cameron NE, Cotter MA 1999 Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes. Diabetes Res Clin Pract 45:137–146[CrossRef][Medline]
104. Mullarkey CJ, Edelstein D, Brownlee M 1990 Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun 173:932–939[CrossRef][Medline]
105. Stevens MJ, Lattimer SA, Kamijo M, VanHuysen C, Sima AAF, Greene DA 1993 Osmotically-induced nerve taurine depletion and the compatible osmolyte hypothesis in experimental diabetic neuropathy in the rat. Diabetologia 36:608–614[CrossRef][Medline]
106. Oates PJ, Mylari BL 1999 Aldose reductase inhibitors: therapeutic implications for diabetic complications. Expert Opin Investig Drugs 8:2095–2119[CrossRef][Medline]
107. Gopalakrishna R, Jaken S 2000 Protein kinase C signaling and oxidative stress. Free Radic Biol Med 28:1349–1361[CrossRef][Medline]
108. Craven PA, DeRubertis FR 1989 Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. Possible mediation by glucose. J Clin Invest 83:1667–1675[Medline]
109. Lee TS, Saltsman KA, Ohashi H, King GL 1989 Activation of protein kinase C by elevation of glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci USA 86:5141–5145[Abstract/Free Full Text]
110. Ishii H, Koya D, King GL 1998 Protein kinase C activation and its role in the development of vascular complication in diabetes mellitus. J Mol Med 76:21–31[CrossRef][Medline]
111. Tomlinson DR 1999 Mitogen-activated protein kinases as glucose transducers for diabetic complications. Diabetologia 42:1271–1281[CrossRef][Medline]
112. Cameron NE, Cotter MA 2002 Effects of protein kinase Cß inhibition on neurovascular dysfunction in diabetic rats: interaction with oxidative stress and essential fatty acid dysmetabolism. Diabetes Metab Res Rev 18:315–323[CrossRef][Medline]
113. Srivastava AK 2002 High glucose-induced activation of protein kinase signaling pathways in vascular smooth muscle cells: a potential role in the pathogenesis of vascular dysfunction in diabetes (review). Int J Mol Med 9:85–89[Medline]
114. Fernyhough P, Gallagher A, Averill SA, Priestley JV, Hounsom L, Patel J, Tomlinson DR 1999 Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. Diabetes 48:881–889[Abstract]
115. Oh-Hashi K, Maruyama W, Isobe K 2001 Peroxynitrite induces GADD34, 45, and 153 VIA p38 MAPK in human neuroblastoma SH-SY5Y cells. Free Radic Biol Med 30:213–221[CrossRef][Medline]
116. Hagen T, Vidal-Puig A 2002 Mitochondrial uncoupling proteins in human physiology and disease. Minerva Med 93:41–57[Medline]
117. Vincent AM, Gong C, Brownlee M, Russell JW, Glucose induced neuronal programmed cell death is regulated by manganese superoxide dismutase and uncoupling protein-1. Program of the 83rd Annual Meeting of The Endocrine Society, Denver, CO, 2001, p 210 (Abstract P1-289)
118. Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD 2002 Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99[CrossRef][Medline]
119. Brown GC 2001 Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta 1504:46–57[Medline]
120. Wright G, Terada K, Yano M, Sergeev I, Mori M 2001 Oxidative stress inhibits the mitochondrial import of preproteins and leads to their degradation. Exp Cell Res 263:107–117[CrossRef][Medline]
121. Kowaltowski AJ, Castilho RF, Vercesi AE 2001 Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15[CrossRef][Medline]
122. Ceriello A, dello Russo P, Amstad P, Cerutti P 1996 High glucose induces antioxidant enzymes in human endothelial cells in culture. Evidence linking hyperglycemia and oxidative stress. Diabetes 45:471–477[Abstract]
123. Kishi Y, Nickander KK, Schmelzer JD, Low PA 2000 Gene expression of antioxidant enzymes in experimental diabetic neuropathy. J Peripher Nerv Syst 5:11–18[CrossRef][Medline]
124. Lissi EA, Salim-Hanna M, Sir T, Videla LA 1992 Is spontaneous urinary visible chemiluminescence a reflection of in vivo oxidative stress? Free Radic Biol Med 12:317–322[CrossRef][Medline]
125. Lissi EA, Salim-Hanna M, Videla LA 1994 Spontaneous urinary visible luminescence: characteristics and modification by oxidative stress-related clinical conditions. Braz J Med Biol Res 27:1491–1505[Medline]
126. Prior RL, Cao G 1999 In vivo total antioxidant capacity: comparison of different analytical methods. Free Radic Biol Med 27:1173–1181[CrossRef][Medline]
127. Ghiselli A, Serafini M, Maiani G, Azzini E, Ferro-Luzzi A 1995 A fluorescence-based method for measuring total plasma antioxidant capability. Free Radic Biol Med 18:29–36[CrossRef][Medline]
128. Benzie IF, Strain JJ 1996 The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Anal Biochem 239:70–76[CrossRef][Medline]
129. Ceriello A, Bortolotti N, Falleti E, Taboga C, Tonutti L, Crescentini A, Motz E, Lizzio S, Russo A, Bartoli E 1997 Total radical-trapping antioxidant parameter in NIDDM patients. Diabetes Care 20:194–197[Abstract]
130. Maxwell SR, Thomason H, Sandler D, Leguen C, Baxter MA, Thorpe GH, Jones AF, Barnett AH 1997 Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur J Clin Invest 27:484–490[CrossRef][Medline]
131. Maxwell SR, Thomason H, Sandler D, Leguen C, Baxter MA, Thorpe GH, Jones AF, Barnett AH 1997 Poor glycaemic control is associated with reduced serum free radical scavenging (antioxidant) activity in non-insulin-dependent diabetes mellitus. Ann Clin Biochem 34:638–644
132. Pop-Busui R, Sullivan KA, Van Huysen C, Bayer L, Cao X, Towns R, Stevens MJ 2001 Depletion of taurine in experimental diabetic neuropathy: implications for nerve metabolic, vascular, and functional deficits. Exp Neurol 168:259–272[CrossRef][Medline]
133. Mulholland CW, Strain JJ 1993 Total radical-trapping antioxidant potential (TRAP) of plasma: effects of supplementation of young healthy volunteers with large doses of -tocopherol and ascorbic acid. Int J Vitam Nutr Res 63:27–30[Medline]
134. Sampson MJ, Gopaul N, Davies IR, Hughes DA, Carrier MJ 2002 Plasma F2 isoprostanes: direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes. Diabetes Care 25:537–541[Abstract/Free Full Text]
135. Obrosova IG, Fathallah L, Greene DA 2000 Early changes in lipid peroxidation and antioxidative defense in diabetic rat retina: effect of DL--lipoic acid. Eur J Pharmacol 398:139–146[CrossRef][Medline]
136. Aydin A, Orhan H, Sayal A, Ozata M, Sahin G, Isimer A 2001 Oxidative stress and nitric oxide related parameters in type II diabetes mellitus: effects of glycemic control. Clin Biochem 34:65–70[CrossRef][Medline]
137. Askar MA, Baquer NZ 1994 Changes in the activity of NADH-oxidase in rat tissues during experimental diabetes. Biochem Mol Biol Int 34:909–914[Medline]
138. Oyama Y, Hayashi A, Ueha T, Maekawa K 1994 Characterization of 2',7'-dichlorofluorescin fluorescence in dissociated mammalian brain neurons: estimation on intracellular content of hydrogen peroxide. Brain Res 635:113–117[CrossRef][Medline]
139. Rothe G, Valet G 1990 Flow cytometric analysis of respiratory burst activity in phagocytes with hydroethidine and 2',7'-dichlorofluorescin. J Leukoc Biol 47:440–448[Abstract]
140. Oldreive C, Bradley N, Bruckdorfer R, Rice-Evans C 2001 Lack of influence of dietary nitrate/nitrite on plasma nitrotyrosine levels measured using a competitive inhibition of binding ELISA assay. Free Radic Res 35:377–386[CrossRef][Medline]
141. Devaraj S, Hirany SV, Burk RF, Jialal I 2001 Divergence between LDL oxidative susceptibility and urinary F(2)-isoprostanes as measures of oxidative stress in type 2 diabetes. Clin Chem 47:1974–1979[Abstract/Free Full Text]
142. Leinonen J, Lehtimaki T, Toyokuni S, Okada K, Tanaka T, Hiai H, Ochi H, Laippala P, Rantalaiho V, Wirta O, Pasternack A, Alho H 1997 New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus. FEBS Lett 417:150–152[CrossRef][Medline]
143. Gopaul NK, Anggard EE, Mallet AI, Betteridge DJ, Wolff SP, Nourooz-Zadeh J 1995 Plasma 8-epi-PGF2 levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Lett 368:225–229[CrossRef][Medline]
144. Poulsen HE, Loft S, Prieme H, Vistisen K, Lykkesfeldt J, Nyyssonen K, Salonen JT 1998 Oxidative DNA damage in vivo: relationship to age, plasma antioxidants, drug metabolism, glutathione-S-transferase activity and urinary creatinine excretion. Free Radic Res 29:565–571[CrossRef][Medline]
145. Dandona P, Thusu K, Cook S, Snyder B, Makowski J, Armstrong D, Nicotera T 1996 Oxidative damage to DNA in diabetes mellitus. Lancet 347:444–445[CrossRef][Medline]
146. Cakatay U, Telci A, Salman S, Satman L, Sivas A 2000 Oxidative protein damage in type I diabetic patients with and without complications. Endocr Res 26:365–379[Medline]
147. Grune T, Blasig IE, Sitte N, Roloff B, Haseloff R, Davies KJ 1998 Peroxynitrite increases the degradation of aconitase and other cellular proteins by proteasome. J Biol Chem 273:10857–10862[Abstract/Free Full Text]
148. Moskovitz J, Yim MB, Chock PB 2002 Free radicals and disease. Arch Biochem Biophys 397:354–359[CrossRef][Medline]
149. Telci A, Cakatay U, Kayali R, Erdogan C, Orhan Y, Sivas A, Akcay T 2000 Oxidative protein damage in plasma of type 2 diabetic patients. Horm Metab Res 32:40–43[Medline]
150. Telci A, Cakatay U, Salman S, Satman I, Sivas A 2000 Oxidative protein damage in early stage type 1 diabetic patients. Diabetes Res Clin Pract 50:213–223[Medline]
151. Molitch ME, Steffes MW, Cleary PA, Nathan DM 1993 Baseline analysis of renal function in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Kidney Int 43:668–674[Medline]
152. Chugh SN, Dhawan R, Kishore K, Sharma A, Chugh K 2001 Glibenclamide vs gliclazide in reducing oxidative stress in patients of noninsulin dependent diabetes mellitus—a double blind randomized study. J Assoc Physicians India 49:803–807[Medline]
153. Sima AAF, Stevens MJ, Feldman EL, Cherian PV, Greene DA 1993 Animal models as tools for the testing of preventive and therapeutic measures in diabetic neuropathy. In: Shafrir E, ed. Lessons from animal diabetes. Vol IV. London: Smith-Gordon; 177–191
154. Obrosova IG, Van Huysen C, Fathallah L, Cao XC, Greene DA, Stevens MJ 2002 An aldose reductase inhibitor reverses early diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense. FASEB J 16:123–125[Abstract/Free Full Text]
155. Cameron NE, Cotter MA, Basso M, Hohman TC 1997 Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats. Diabetologia 40:271–281[CrossRef][Medline]
156. Yamamoto T, Takakura S, Kawamura I, Seki J, Goto T 2001 The effects of zenarestat, an aldose reductase inhibitor, on minimal F-wave latency and nerve blood flow in streptozotocin-induced diabetic rats. Life Sci 68:1439–1448[CrossRef][Medline]
157. Shimoshige Y, Ikuma K, Yamamoto T, Takakura S, Kawamura I, Seki J, Mutoh S, Goto T 2000 The effects of zenarestat, an aldose reductase inhibitor, on peripheral neuropathy in Zucker diabetic fatty rats. Metabolism 49:1395–1399[CrossRef][Medline]
158. Greene DA, Arezzo JC, Brown MB 1999 Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology 53:580–591[Abstract/Free Full Text]
159. Obrosova IG, Minchenko AG, Vasupuram R, White L, Abatan OI, Kumagai AK, Frank RN, Stevens MJ 2003 Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats. Diabetes 52:864–871[Abstract/Free Full Text]
160. Hotta N, Toyota T, Matsuoka K, Shigeta Y, Kikkawa R, Kaneko T, Takahashi A, Sugimura K, Koike Y, Ishii J, Sakamoto N 2001 Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study. Diabetes Care 24:1776–1782[Abstract/Free Full Text]
161. Asano T, Saito Y, Kawakami M, Yamada N 2002 Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients. J Diabetes Complications 16:133–138[CrossRef][Medline]
162. Apfel SC 2002 Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? Int Rev Neurobiol 50:393–413[Medline]
163. Cruz-Aguado R, Turner LF, Diaz CM, Pinero J 2000 Nerve growth factor and striatal glutathione metabolism in a rat model of Huntington’s disease. Restor Neurol Neurosci 17:217–221[Medline]
164. Thippeswamy T, Morris R 1997 Nerve growth factor inhibits the expression of nitric oxide synthase in neurones in dissociated cultures of rat dorsal root ganglia. Neurosci Lett 230:9–12[CrossRef][Medline]
165. Calcutt NA 2002 Future treatments for diabetic neuropathy: clues from experimental neuropathy. Curr Diab Rep 2:482–488[Medline]
166. Paolisso G, D’Amore A, Balbi V, Volpe C, Galzerano D, Giugliano D, Sgambato S, Varricchio M, D’Onofrio F 1994 Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics. Am J Physiol 266:E261–E268
167. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, Augustin HJ, Dietze GJ 1995 Enhancement of glucose disposal in patients with type 2 diabetes by -lipoic acid. Arzneimittelforschung 45:872–874[Medline]
168. Natarajan Sulochana K, Lakshmi S, Punitham R, Arokiasamy T, Sukumar B, Ramakrishnan S 2002 Effect of oral supplementation of free amino acids in type 2 diabetic patients—a pilot clinical trial. Med Sci Monit 8:CR131–CR137
169. Henriksen EJ, Saengsirisuwan V 2003 Exercise training and antioxidants: relief from oxidative stress and insulin resistance. Exerc Sport Sci Rev 31:79–84[CrossRef][Medline]
170. Wan Nazaimoon WM, Khalid BA 2002 Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats. Malays J Pathol 24:77–82[Medline]
171. Packer L, Tritschler HJ, Wessel K 1997 Neuroprotection by the metabolic antioxidant -lipoic acid. Free Radic Biol Med 22:359–378[CrossRef][Medline]
172. Cameron NE, Cotter MA, Horrobin DH, Tritschler HJ 1998 Effects of -lipoic acid on neurovascular function in diabetic rats: interaction with essential fatty acids. Diabetologia 41:390–399[CrossRef][Medline]
173. Obrosova I, Cao X, Greene DA, Stevens MJ 1998 Diabetes-induced changes in lens antioxidant status, glucose utilization and energy metabolism: effect of DL--lipoic acid. Diabetologia 41:1442–1450[CrossRef][Medline]
174. Stevens MJ, Obrosova I, Cao X, Van Huysen C, Greene DA 2000 Effects of DL--lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy. Diabetes 49:1006–1015[Abstract]
175. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA 2001 Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 50:1927–1937[Abstract/Free Full Text]
176. Dincer Y, Telci A, Kayali R, Yilmaz IA, Cakatay U, Akcay T 2002 Effect of -lipoic acid on lipid peroxidation and anti-oxidant enzyme activities in diabetic rats. Clin Exp Pharmacol Physiol 29:281–284[CrossRef][Medline]
177. Maritim AC, Sanders RA, Watkins III JB 2003 Effects of -lipoic acid on biomarkers of oxidative stress in streptozotocin-induced diabetic rats. J Nutr Biochem 14:288–294[CrossRef][Medline]
178. Piotrowski P, Wierzbicka K, Smialek M 2001 Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia treated with antioxidants. Folia Neuropathol 39:147–154[Medline]
179. Midaoui AE, Elimadi A, Wu L, Haddad PS, de Champlain J 2003 Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production. Am J Hypertens 16:173–179[CrossRef][Medline]
180. Borcea V, Nourooz-Zadeh J, Wolff SP, Klevesath M, Hofmann M, Urich H, Wahl P, Ziegler R, Tritschler H, Halliwell B, Nawroth PP 1999 -Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria. Free Radic Biol Med 26:1495–1500[CrossRef][Medline]
181. Haak E, Usadel KH, Kusterer K, Amini P, Frommeyer R, Tritschler HJ, Haak T 2000 Effects of -lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Exp Clin Endocrinol Diabetes 108:168–174[CrossRef][Medline]
182. Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R 1999 Treatment of symptomatic diabetic polyneuropathy with the antioxidant -lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. -Lipoic acid in diabetic neuropathy. Diabetes Care 22:1296–1301[Abstract]
183. Ziegler D, Reljanovic M, Mehnert H, Gries FA 1999 -Lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes 107:421–430[Medline]
184. Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G 1997 Effects of treatment with the antioxidant -lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care 20:369–373[Abstract]
185. Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O’Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D 2003 The sensory symptoms of diabetic polyneuropathy are improved with -lipoic acid: the SYDNEY trial. Diabetes Care 26:770–776[Abstract/Free Full Text]
186. Paolisso G, Balbi V, Volpe C, Varricchio G, Gambardella A, Saccomanno F, Ammendola S, Varricchio M, D’Onofrio F 1995 Metabolic benefits deriving from chronic vitamin C supplementation in aged non-insulin dependent diabetics. J Am Coll Nutr 14:387–392[Abstract]
187. Je HD, Shin CY, Park HS, Huh IH, Sohn UD 2001 The comparison of vitamin C and vitamin E on the protein oxidation of diabetic rats. J Auton Pharmacol 21:231–236[CrossRef][Medline]
188. Shinozaki K, Takeda H, Inazu M, Matsumiya T, Takasaki M 2002 Abnormal incorporation and utilization of -tocopherol in erythrocyte membranes of streptozotocin-induced diabetic rats. Eur J Pharmacol 456:133–139[CrossRef][Medline]
189. Li D, Devaraj S, Fuller C, Bucala R, Jialal I 1996 Effect of -tocopherol on LDL oxidation and glycation: in vitro and in vivo studies. J Lipid Res 37:1978–1986[Abstract]
190. Celik S, Baydas G, Yilmaz O 2002 Influence of vitamin E on the levels of fatty acids and MDA in some tissues of diabetic rats. Cell Biochem Funct 20:67–71[CrossRef][Medline]
191. Rosen P, Ballhausen T, Bloch W, Addicks K 1995 Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant. Diabetologia 38:1157–1168[Medline]
192. Baydas G, Nedzvetskii VS, Tuzcu M, Yasar A, Kirichenko SV 2003 Increase of glial fibrillary acidic protein and S-100B in hippocampus and cortex of diabetic rats: effects of vitamin E. Eur J Pharmacol 462:67–71[CrossRef][Medline]
193. Ulusu NN, Sahilli M, Avci A, Canbolat O, Ozansoy G, Ari N, Bali M, Stefek M, Stolc S, Gajdosik A, Karasu C 2003 Pentose phosphate pathway, glutathione-dependent enzymes and antioxidant defense during oxidative stress in diabetic rodent brain and peripheral organs: effects of stobadine and vitamin E. Neurochem Res 28:815–823[CrossRef][Medline]
194. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Keaney JF, Creager MA 2003 Oral antioxidant therapy improves endothelial function in type 1 but not type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 285:H2392–H2398
195. Fuller CJ, Chandalia M, Garg A, Grundy SM, Jialal I 1996 RRR--tocopheryl acetate supplementation at pharmacologic doses decreases low-density-lipoprotein oxidative susceptibility but not protein glycation in patients with diabetes mellitus. Am J Clin Nutr 63:753–759[Abstract/Free Full Text]
196. Ruffini I, Belcaro G, Cesarone MR, Geroulakos G, Di Renzo A, Milani M, Coen L, Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, Griffin M, Ippolito E, Bavera P 2003 Evaluation of the local effects of vitamin E (E-Mousse) on free radicals in diabetic microangiopathy: a randomized, controlled trial. Angiology 54:415–421[Medline]
197. Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C 1999 In vivo formation of 8-iso-prostaglandin f2 and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 99:224–229[Abstract/Free Full Text]
198. Hasanain B, Mooradian AD 2002 Antioxidant vitamins and their influence in diabetes mellitus. Curr Diab Rep 2:448–456[Medline]
199. Sung L, Greenberg ML, Koren G, Tomlinson GA, Tong A, Malkin D, Feldman BM 2003 Vitamin E: the evidence for multiple roles in cancer. Nutr Cancer 46:1–14[CrossRef][Medline]
200. Huang HY, Appel LJ 2003 Supplementation of diets with -tocopherol reduces serum concentrations of - and -tocopherol in humans. J Nutr 133:3137–3140[Abstract/Free Full Text]
201. Min J, Guo J, Zhao F, Cai D 2003 [Effect of apoptosis induced by different vitamin E homologous analogues in human hepatoma cells(HepG2)]. Wei Sheng Yan Jiu 32:343–345 (Chinese)[Medline]
202. Opara EC 2002 Oxidative stress, micronutrients, diabetes mellitus and its complications. J R Soc Health 122:28–34[Medline]
203. Meister A 1991 Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther 51:155–194[CrossRef][Medline]
204. Halat KM, Dennehy CE 2003 Botanicals and dietary supplements in diabetic peripheral neuropathy. J Am Board Fam Pract 16:47–57[Abstract/Free Full Text]
205. Honma H, Podratz JL, Windebank AJ 2003 Acute glucose deprivation leads to apoptosis in a cell model of acute diabetic neuropathy. J Peripher Nerv Syst 8:65–74[CrossRef][Medline]
206. Feldman EL 2003 Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest 111:431–433[CrossRef][Medline]
207. Ueno Y, Kizaki M, Nakagiri R, Kamiya T, Sumi H, Osawa T 2002 Dietary glutathione protects rats from diabetic nephropathy and neuropathy. J Nutr 132:897–900[Abstract/Free Full Text]
208. Giardino I, Fard AK, Hatchell DL, Brownlee M 1998 Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation, and oxidant-induced apoptosis. Diabetes 47:1114–1120[Abstract]
209. Cameron NE, Cotter MA, Archibald V, Dines KC, Maxfield EK 1994 Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats. Diabetologia 37:449–459[CrossRef][Medline]
210. Karasu Ç, Dewhurst M, Stevens EJ, Tomlinson DR 1995 Effects of anti-oxidant treatment on sciatic nerve dysfunction in streptozotocin-diabetic rats; comparison with essential fatty acids. Diabetologia 38:129–134[Medline]
211. Obrosova IG, Stevens MJ 1999 Effect of dietary taurine supplementation on GSH and NAD(P)-redox status, lipid peroxidation, and energy metabolism in diabetic precataractous lens. Invest Ophthalmol Vis Sci 40:680–688[Abstract/Free Full Text]
212. Sagara M, Satoh J, Wada R, Yagihashi S, Takahashi K, Fukuzawa M, Muto G, Muto Y, Toyota T 1996 Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine. Diabetologia 39:263–269[Medline]
213. Pieper GM, Siebeneich W 1998 Oral administration of the antioxidant, N-acetylcysteine, abrogates diabetes-induced endothelial dysfunction. J Cardiovasc Pharmacol 32:101–105[CrossRef][Medline]
214. Cameron NE, Cotter MA, Maxfield EK 1993 Anti-oxidant treatment prevents the development of peripheral nerve dysfunction in streptozotocin-diabetic rats. Diabetologia 36:299–304[CrossRef][Medline]
215. Butler R, Morris AD, Belch JJ, Hill A, Struthers AD 2000 Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35:746–751[Abstract/Free Full Text]
216. Manuel y Keenoy B, Vertommen J, De Leeuw I 1999 The effect of flavonoid treatment on the glycation and antioxidant status in type 1 diabetic patients. Diabetes Nutr Metab 12:256–263.[Medline]
217. Lubec B, Hayn M, Kitzmuller E, Vierhapper H, Lubec G 1997 L-Arginine reduces lipid peroxidation in patients with diabetes mellitus. Free Radic Biol Med 22:355–357[CrossRef][Medline]
218. Faure P, Benhamou PY, Perard A, Halimi S, Roussel AM 1995 Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: effects of an oral zinc supplementation. Eur J Clin Nutr 49:282–288[Medline]

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