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Eva L. Feldman - One of the best experts on this subject based on the ideXlab platform.
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Diabetic Neuropathy.
Nature reviews. Disease primers, 2019Co-Authors: Eva L. Feldman, Brian C. Callaghan, Rodica Pop-busui, Douglas W Zochodne, Douglas E Wright, David L Bennett, Vera Bril, James W Russell, Vijay ViswanathanAbstract:The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is Neuropathy, of which distal symmetric polyNeuropathy (for the purpose of this Primer, referred to as Diabetic Neuropathy) is very common. Diabetic Neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop Diabetic Neuropathy. Glucose control effectively halts the progression of Diabetic Neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of Diabetic Neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful Diabetic Neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of Diabetic Neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying Neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of Diabetic Neuropathy, from prevention to treatment.
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Diabetic Neuropathy: A Position Statement by the American Diabetes Association
Diabetes care, 2016Co-Authors: Rodica Pop-busui, Eva L. Feldman, Vera Bril, Rayaz A. Malik, Andrew J.m. Boulton, Roy Freeman, Jay M. Sosenko, Dan ZieglerAbstract:Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of Neuropathy in the patient with diabetes is important for a number of reasons: 1. Diabetic Neuropathy is a diagnosis of exclusion. NonDiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures. 2. A number of treatment options exist for symptomatic Diabetic Neuropathy. 3. Up to 50% of Diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet. 4. Recognition and treatment of autonomic Neuropathy may improve symptoms, reduce sequelae, and improve quality of life. Among the various forms of Diabetic Neuropathy, distal symmetric polyNeuropathy (DSPN) and Diabetic autonomic neuropathies, particularly cardiovascular autonomic Neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of Diabetic Neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to Diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the Diabetic neuropathies. View this table: Table 1 Classification for Diabetic neuropathies Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of Diabetic Neuropathy is also critical in clinical practice, as it may detect the earliest stages of Neuropathy, enabling early intervention. Although screening for rarer atypical forms of Diabetic Neuropathy may be warranted, DSPN and autonomic Neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms. This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …
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Diabetic Neuropathy: cellular mechanisms as therapeutic targets
Nature Reviews Neurology, 2011Co-Authors: Andrea M Vincent, Andrea L. Smith, Brian C. Callaghan, Eva L. FeldmanAbstract:Neuropathy is the most common complication of diabetes and considerably reduces patient quality of life, yet no disease-modifying therapies are currently available and symptomatic treatments generally provide only partial relief. Vincent and colleagues provide an update on the cellular mechanisms that lead to Diabetic Neuropathy, which involves a complex interplay between oxidative and inflammatory pathways in neurons, Schwann cells and the microvascular endothelium. The authors highlight potential new therapeutic targets and discuss drug candidates that are in development for this debilitating Diabetic complication. In patients with diabetes, nerve injury is a common complication that leads to chronic pain, numbness and substantial loss of quality of life. Good glycemic control can decrease the incidence of Diabetic Neuropathy, but more than half of all patients with diabetes still develop this complication. There is no approved treatment to prevent or halt Diabetic Neuropathy, and only symptomatic pain therapies, with variable efficacy, are available. New insights into the mechanisms leading to the development of Diabetic Neuropathy continue to point to systemic and cellular imbalances in metabolites of glucose and lipids. In the PNS, sensory neurons, Schwann cells and the microvascular endothelium are vulnerable to oxidative and inflammatory stress in the presence of these altered metabolic substrates. This Review discusses the emerging cellular mechanisms that are activated in the Diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling. We highlight the pathways to cellular injury, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation. Multiple metabolic imbalances underlie the development of Diabetic Neuropathy Hyperglycemia, dyslipidemia and cardiovascular dysfunction are each independent risk factors for Neuropathy Targeting risk factors as well as cellular oxidative stress and inflammation will be important in future treatment approaches Injury to neurons, Schwann cells and microvascular endothelial cells in the Diabetic milieu contributes to the pathogenesis of Neuropathy
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Diabetic Neuropathy cellular mechanisms as therapeutic targets
Nature Reviews Neurology, 2011Co-Authors: Andrea M Vincent, Andrea L. Smith, Brian C. Callaghan, Eva L. FeldmanAbstract:In patients with diabetes, nerve injury is a common complication that leads to chronic pain, numbness and substantial loss of quality of life. Good glycemic control can decrease the incidence of Diabetic Neuropathy, but more than half of all patients with diabetes still develop this complication. There is no approved treatment to prevent or halt Diabetic Neuropathy, and only symptomatic pain therapies, with variable efficacy, are available. New insights into the mechanisms leading to the development of Diabetic Neuropathy continue to point to systemic and cellular imbalances in metabolites of glucose and lipids. In the PNS, sensory neurons, Schwann cells and the microvascular endothelium are vulnerable to oxidative and inflammatory stress in the presence of these altered metabolic substrates. This Review discusses the emerging cellular mechanisms that are activated in the Diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling. We highlight the pathways to cellular injury, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation.
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Mechanisms of disease: The oxidative stress theory of Diabetic Neuropathy
Reviews in Endocrine and Metabolic Disorders, 2008Co-Authors: Claudia Figueroa-romero, Mahdieh Sadidi, Eva L. FeldmanAbstract:Diabetic Neuropathy is the most common complication of diabetes, affecting 50% of Diabetic patients. Currently, the only treatment for Diabetic Neuropathy is glucose control and careful foot care. In this review, we discuss the idea that excess glucose overloads the electron transport chain, leading to the production of superoxides and subsequent mitochondrial and cytosolic oxidative stress. Defects in metabolic and vascular pathways intersect with oxidative stress to produce the onset and progression of nerve injury present in Diabetic Neuropathy. These pathways include the production of advanced glycation end products, alterations in the sorbitol, hexosamine and protein kinase C pathways and activation of poly-ADP ribose polymerase. New bioinformatics approaches can augment current research and lead to new discoveries to understand the pathogenesis of Diabetic Neuropathy and to identify more effective molecular therapeutic targets.
Rayaz A. Malik - One of the best experts on this subject based on the ideXlab platform.
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Diabetic Neuropathy: A focus on small fibres
Diabetes Metabolism Research and Reviews, 2019Co-Authors: Rayaz A. MalikAbstract:Diabetic peripheral Neuropathy (DPN) is diagnosed too late, which contrasts with our approach for Diabetic retinopathy and nephropathy, where incipient disease is detected early enabling timely treatment. The 10-g monofilament and a foot exam are the commonly used methods for screening Diabetic Neuropathy, but this primarily identifies moderate to severe Diabetic Neuropathy. Small fibres are damaged early and are associated with the development of painful Diabetic Neuropathy, foot ulceration, and Charcot foot. Tests of small fibre damage include thermal thresholds, microneurography, evoked potentials, sudomotor function, laser Doppler flare, skin biopsy, and corneal confocal microscopy. Measures of small fibre damage and repair may be key to the assessment of efficacy in clinical trials of disease modifying therapies for Diabetic Neuropathy.
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mirogabalin and emerging therapies for Diabetic Neuropathy
Journal of Pain Research, 2018Co-Authors: Saad Ahmed Javed, Uazman Alam, Rayaz A. MalikAbstract:There are currently no approved disease-modifying therapies for Diabetic Neuropathy, and there are only 3 US Food and Drug Administration-approved therapies (pregabalin, duloxetine, and tapentadol) for painful Diabetic Neuropathy. They each have moderate efficacy with adverse effects limiting optimal dose titration. There is a considerable need for new therapies for the management of painful Diabetic Neuropathy. We reviewed the potential role of mirogabalin, which like gabapentin and pregabalin modulates the alpha-2/delta-1 subunit of the voltage-gated calcium channel, allowing the influx of calcium and release of neurotransmitters at the synaptic cleft in the central nervous system and spinal cord. It has shown efficacy and good tolerability in a Phase II study in Diabetic painful Neuropathy and based on the results of two Phase III clinical trials in Diabetic painful Neuropathy and post-herpetic neuralgia, Daiichi Sankyo submitted a marketing application for neuropathic pain in Japan in February 2018. We have also reviewed potential new therapies, currently in Phase II clinical trials that may modify disease and/or relieve neuropathic pain through novel modes of action.
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Diabetic Neuropathy: A Position Statement by the American Diabetes Association
Diabetes care, 2016Co-Authors: Rodica Pop-busui, Eva L. Feldman, Vera Bril, Rayaz A. Malik, Andrew J.m. Boulton, Roy Freeman, Jay M. Sosenko, Dan ZieglerAbstract:Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of Neuropathy in the patient with diabetes is important for a number of reasons: 1. Diabetic Neuropathy is a diagnosis of exclusion. NonDiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures. 2. A number of treatment options exist for symptomatic Diabetic Neuropathy. 3. Up to 50% of Diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet. 4. Recognition and treatment of autonomic Neuropathy may improve symptoms, reduce sequelae, and improve quality of life. Among the various forms of Diabetic Neuropathy, distal symmetric polyNeuropathy (DSPN) and Diabetic autonomic neuropathies, particularly cardiovascular autonomic Neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of Diabetic Neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to Diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the Diabetic neuropathies. View this table: Table 1 Classification for Diabetic neuropathies Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of Diabetic Neuropathy is also critical in clinical practice, as it may detect the earliest stages of Neuropathy, enabling early intervention. Although screening for rarer atypical forms of Diabetic Neuropathy may be warranted, DSPN and autonomic Neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms. This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …
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Pathology of human Diabetic Neuropathy.
Handbook of clinical neurology, 2014Co-Authors: Rayaz A. MalikAbstract:Pathologic study of a disease provides insights into the precise mechanisms and targets of damage and may provide insights into new therapies. The main targets in Diabetic Neuropathy are myelinated and unmyelinated fibers as dysfunction and damage to them explains the symptoms of painful Neuropathy and the major end points of foot ulceration and amputation as well as mortality. Demyelination and axonal degeneration are established hallmarks of the pathology of human Diabetic Neuropathy and were derived from pioneering light and electronmicroscopic studies of sural nerve biopsies in the late 1960s and early 1970s. Additional abnormalities, which are relevant to the pathogenesis of human Diabetic Neuropathy, include pathology of the microvessels and extracellular space. Intraepidermal and sudomotor nerve quantification in skin biopsies provides a minimally invasive means for the detection of early nerve damage. Studies of muscle biopsies are limited and show significant alterations in the expression of neurotrophins, but limited changes in muscle fiber size and capillary density.
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Corneal markers of Diabetic Neuropathy
2011Co-Authors: Nicola Pritchard, Rayaz A. Malik, Katie Edwards, Ayda M. Shahidi, Geoff P. Sampson, Anthony W. Russell, Nathan EfronAbstract:Diabetic Neuropathy is a significant clinical problem that currently has no effective therapy, and in advanced cases, leads to foot ulceration and lower limb amputation. The accurate detection, characterization and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression, and assess new therapies This review evaluates novel corneal methods of assessing Diabetic Neuropathy. Two new non-invasive corneal markers have emerged, and in cross-sectional studies have demonstrated their ability to stratify the severity of this disease. Corneal confocal microscopy allows quantification of corneal nerve parameters and non-contact corneal esthesiometry, the functional correlate of corneal structure, assesses the sensitivity of the cornea. Both these techniques are quick to perform, produce little or no discomfort for the patient, and are suitable for clinical settings. Each has advantages and disadvantages over traditional techniques for assessing Diabetic Neuropathy. Application of these new corneal markers for longitudinal evaluation of Diabetic Neuropathy has the potential to reduce dependence on more invasive, costly, and time-consuming assessments, such as skin biopsy.
Andrea M Vincent - One of the best experts on this subject based on the ideXlab platform.
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Diabetic Neuropathy: cellular mechanisms as therapeutic targets
Nature Reviews Neurology, 2011Co-Authors: Andrea M Vincent, Andrea L. Smith, Brian C. Callaghan, Eva L. FeldmanAbstract:Neuropathy is the most common complication of diabetes and considerably reduces patient quality of life, yet no disease-modifying therapies are currently available and symptomatic treatments generally provide only partial relief. Vincent and colleagues provide an update on the cellular mechanisms that lead to Diabetic Neuropathy, which involves a complex interplay between oxidative and inflammatory pathways in neurons, Schwann cells and the microvascular endothelium. The authors highlight potential new therapeutic targets and discuss drug candidates that are in development for this debilitating Diabetic complication. In patients with diabetes, nerve injury is a common complication that leads to chronic pain, numbness and substantial loss of quality of life. Good glycemic control can decrease the incidence of Diabetic Neuropathy, but more than half of all patients with diabetes still develop this complication. There is no approved treatment to prevent or halt Diabetic Neuropathy, and only symptomatic pain therapies, with variable efficacy, are available. New insights into the mechanisms leading to the development of Diabetic Neuropathy continue to point to systemic and cellular imbalances in metabolites of glucose and lipids. In the PNS, sensory neurons, Schwann cells and the microvascular endothelium are vulnerable to oxidative and inflammatory stress in the presence of these altered metabolic substrates. This Review discusses the emerging cellular mechanisms that are activated in the Diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling. We highlight the pathways to cellular injury, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation. Multiple metabolic imbalances underlie the development of Diabetic Neuropathy Hyperglycemia, dyslipidemia and cardiovascular dysfunction are each independent risk factors for Neuropathy Targeting risk factors as well as cellular oxidative stress and inflammation will be important in future treatment approaches Injury to neurons, Schwann cells and microvascular endothelial cells in the Diabetic milieu contributes to the pathogenesis of Neuropathy
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Diabetic Neuropathy cellular mechanisms as therapeutic targets
Nature Reviews Neurology, 2011Co-Authors: Andrea M Vincent, Andrea L. Smith, Brian C. Callaghan, Eva L. FeldmanAbstract:In patients with diabetes, nerve injury is a common complication that leads to chronic pain, numbness and substantial loss of quality of life. Good glycemic control can decrease the incidence of Diabetic Neuropathy, but more than half of all patients with diabetes still develop this complication. There is no approved treatment to prevent or halt Diabetic Neuropathy, and only symptomatic pain therapies, with variable efficacy, are available. New insights into the mechanisms leading to the development of Diabetic Neuropathy continue to point to systemic and cellular imbalances in metabolites of glucose and lipids. In the PNS, sensory neurons, Schwann cells and the microvascular endothelium are vulnerable to oxidative and inflammatory stress in the presence of these altered metabolic substrates. This Review discusses the emerging cellular mechanisms that are activated in the Diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling. We highlight the pathways to cellular injury, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation.
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Diabetic Neuropathy: mechanisms to management.
Pharmacology & therapeutics, 2008Co-Authors: James L. Edwards, Andrea M Vincent, Hsinlin T. Cheng, Eva L. FeldmanAbstract:Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Diabetic Neuropathy encompasses a variety of forms whose impact ranges from discomfort to death. Hyperglycemia induces oxidative stress in Diabetic neurons and results in activation of multiple biochemical pathways. These activated pathways are a major source of damage and are potential therapeutic targets in Diabetic Neuropathy. Though therapies are available to alleviate the symptoms of Diabetic Neuropathy, few options are available to eliminate the root causes. The immense physical, psychological, and economic cost of Diabetic Neuropathy underscore the need for causally targeted therapies. This review covers the pathology, epidemiology, biochemical pathways, and prevention of Diabetic Neuropathy, as well as discusses current symptomatic and causal therapies and novel approaches to identify therapeutic targets.
Ryuichi Kikkawa - One of the best experts on this subject based on the ideXlab platform.
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Diabetic Neuropathy and nerve regeneration.
Progress in neurobiology, 2003Co-Authors: Hitoshi Yasuda, Masahiko Terada, Kengo Maeda, Shuro Kogawa, Mitsuru Sanada, Masakazu Haneda, Atsunori Kashiwagi, Ryuichi KikkawaAbstract:Diabetic Neuropathy is the most common peripheral Neuropathy in western countries. Although every effort has been made to clarify the pathogenic mechanism of Diabetic Neuropathy, thereby devising its ideal therapeutic drugs, neither convinced hypotheses nor unequivocally effective drugs have been established. In view of the pathologic basis for the treatment of Diabetic Neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. Nerve regeneration or sprouting in diabetes may occur not only in the nerve trunk but also in the dermis and around dorsal root ganglion neurons, thereby being implicated in the generation of pain sensation. Thus, inadequate nerve regeneration unequivocally contributes to the pathophysiologic mechanism of Diabetic Neuropathy. In this context, the research on nerve regeneration in diabetes should be more accelerated. Indeed, nerve regenerative capacity has been shown to be decreased in Diabetic patients as well as in Diabetic animals. Disturbed nerve regeneration in diabetes has been ascribed at least in part to all or some of decreased levels of neurotrophic factors, decreased expression of their receptors, altered cellular signal pathways and/or abnormal expression of cell adhesion molecules, although the mechanisms of their changes remain almost unclear. In addition to their steady-state changes in diabetes, nerve injury induces injury-specific changes in individual neurotrophic factors, their receptors and their intracellular signal pathways, which are closely linked with altered neuronal function, varying from neuronal survival and neurite extension/nerve regeneration to apoptosis. Although it is essential to clarify those changes for understanding the mechanism of disturbed nerve regeneration in diabetes, very few data are now available. Rationally accepted replacement therapy with neurotrophic factors has not provided any success in treating Diabetic Neuropathy. Aside from adverse effects of those factors, more rigorous consideration for their delivery system may be needed for any possible success. Although conventional therapeutic drugs like aldose reductase (AR) inhibitors and vasodilators have been shown to enhance nerve regeneration, their efficacy should be strictly evaluated with respect to nerve regenerative capacity. For this purpose, especially clinically, skin biopsy, by which cutaneous nerve pathology including nerve regeneration can be morphometrically evaluated, might be a safe and useful examination.
James D Schmelzer - One of the best experts on this subject based on the ideXlab platform.
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gene expression of antioxidant enzymes in experimental Diabetic Neuropathy
Journal of The Peripheral Nervous System, 2000Co-Authors: Yutaka Kishi, Kim K Nickander, James D SchmelzerAbstract:Chronic hyperglycemia results in a large deficit in nerve blood flow. Both autoxidative- and ischemia-induced lipid peroxidation occurs, with resultant peripheral sensory Neuropathy in streptozotocin-induced diabetes in the rat. Free radical defenses, especially involving antioxidant enzymes, have been suggested to be reduced, but scant information is available on chronic hyperglycemia. We evaluated the gene expression of glutathione peroxidase, catalase, and superoxide dismutase (cuprozinc and manganese separately) in L4,5 dorsal root ganglion (DRG) and superior cervical ganglion, as well as enzyme activity of glutathione peroxidase in DRG and sciatic nerve in experimental Diabetic Neuropathy of 3 months and 12 months durations. We also evaluated nerve electrophysiology of caudal, sciatic-tibial, and digital nerves. A nerve conduction deficit was seen in all nerves in experimental Diabetic Neuropathy at both 3 and 12 months. Gene expression of glutathione peroxidase, catalase, cuprozinc superoxide dismutase, and manganese superoxide dismutase were not reduced in experimental Diabetic Neuropathy at either 3 or 12 months. Catalase mRNA was significantly increased in experimental Diabetic Neuropathy at 12 months. Glutathione peroxidase enzyme activity was normal in sciatic nerve. We conclude that gene expression is not reduced in peripheral nerve tissues in very chronic experimental Diabetic Neuropathy. Changes in enzyme activity may be related to duration of diabetes or due to post-translational modifications.
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effect of cilostazol on experimental Diabetic Neuropathy in the rat
Diabetologia, 1995Co-Authors: M. Kihara, James D SchmelzerAbstract:Two proposed mechanisms of Diabetic Neuropathy are microvascular ischaemia and a reduction in Na,K-ATPase activity. We evaluated the effect of cilostazol, a drug that is both a potent phosphodiesterase inhibitor that normalizes nerve Na,K-AT-Pase and a vasodilator, on nerve blood flow (NBF) to determine whether it would improve experimental Diabetic Neuropathy. We examined whether epineurally applied cilostazol acted as a vasodilator on the peripheral nerve of normal and Diabetic rats, and whether feeding the rats a cilostazol-supplemented diet could improve Diabetic Neuropathy. Cilostazol increased nerve blood flow (NBF) in a dose-dependent fashion with an EC50 of 10−5.74 mol/l. Cilostazol also normalized NBF in experimental Diabetic Neuropathy with a 10−4 mol/l local application on the sciatic nerve. In Diabetic Neuropathy, a cilostazol-supplemented diet improved both NBF and nerve conduction in a dose- and time-dependent fashion. Potential mechanisms of action of cilostazol on the nerve include its effect on NBF, Na, K-ATPase, and restoration of the thromboxane:prostacyclin ratio. Cilostazol may have potential in the treatment of Diabetic Neuropathy.