Effects of sorbitol dehydrogenase deficiency on nerve conduction in experimental diabetic mice.

Ng, Talwalkar; Lee, F K; Song, Zhen; Calcutt, Nigel A.; Lee, A Y; Chung, SK; Ng, Desai; Lee, L W

doi:10.2337/diabetes.47.6.961

Cited by 65 publications

(52 citation statements)

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“…This is somewhat surprising since it has been shown that SD inhibition using an SD inhibitor, CP470711, can protect ischemic myocardium (Hwang et al, 2003). However, our previous studies on SD À/À mice in experimental diabetes suggested that SD is not a major culprit in the pathogenesis of diabetic neuropathy (Ng et al, 1998). …”

Section: Discussionmentioning

confidence: 97%

“…C57BL/6N mice were also used in experiments with drug treatment. In addition, SD À/À (C57BL/LiA) mice and their age-matched wild-type controls (SD + / + ) were generated by crossing of the SD heterozygous mice (Ng et al, 1998). All animals used were male mice and were housed under diurnal lighting condition and allowed access to food and water ad libitum.…”

Section: Animalsmentioning

confidence: 99%

“…To elucidate the role of the polyol pathway enzymes, AR and SD, in cerebral ischemia and related oxidative stress, we challenged AR-and SD-mutant mice (Ho et al, 2000;Ng et al, 1998) with ischemia/reperfusion injury. The findings that various agents can decrease cerebral infarct size after 2 h of middle cerebral artery occlusion (MCAO) with 22-h reperfusion (Ellsworth et al, 2003;Endres et al, 1998a) suggest that such ischemia-induced brain injury can still be reversed.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Deletion of Aldose Reductase Leads to Protection against Cerebral Ischemic Injury

Cheung

Hung

et al. 2007

J Cereb Blood Flow Metab

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Previously, we reported that transgenic mice overexpressing endothelin-1 in astrocytes showed more severe neurological deficits and increased infarct after transient focal ischemia. In those studies, we also observed increased level of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which has been implicated in osmotic and oxidative stress. To further understand the involvement of the polyol pathway, the mice with deletion of enzymes in the polyol pathway, AR, and sorbitol dehydrogenase (SD), which is the second enzyme in this pathway, were challenged with similar cerebral ischemic injury. Deletion of AR-protected animals from severe neurological deficits and large infarct, whereas similar protection was not observed in mice with SD deficiency. Most interestingly, AR À/À brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR À/À brain was also associated with less poly(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 activation. Pharmacological inhibition of AR by Fidarestat also protected animals against cerebral ischemic injury. These findings are the first to show that AR contributes to iron-and transferrin-related oxidative stress associated with cerebral ischemic injury, suggesting that inhibition of AR but not SD may have therapeutic potential against cerebral ischemic injury.

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Section: Discussionmentioning

confidence: 97%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deletion of Aldose Reductase Leads to Protection against Cerebral Ischemic Injury

Cheung

Hung

et al. 2007

J Cereb Blood Flow Metab

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“…Numerous preclinical studies have demonstrated that inhibition of aldose reductase (the first enzyme in the polyol pathway) prevents almost all manifestations of neuropathy. Studies in which expression of enzymes involved in the polyol pathway has been manipulated have placed a particular focus on the metabolic consequences of excessive metabolism of glucose to sorbitol owing to high activity of aldose reductase [35][36][37][38] . On the basis of the involvement of the polyol pathway, the perception of diabetic neuropathy as a micro vascular complication of diabetes has been underpinned by immunocytochemical studies that showed localization of aldose reductase to the endothelial cells of epineurial and dorsal root ganglion blood vessels and to perivascular sympathetic axons [39][40][41] .…”

Section: Schwann Cells In Diabetic Neuropathymentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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“…According to the concept of ªdiabetic pseudohypoxiaº [28], the increased flux through SDH accounts for NAD-redox imbalances (increase in NADH:NAD + ratio) related to diabetes and constitutes a universal mechanism for development of diabetic complications including neuropathy, retinopathy and nephropathy. Studies of the role for SDH in diabetic complications using SDH inhibitors (SDIs) [4,30,31] as well as a SDH-deficient mouse model [32] resulted in contradictory findings. Some groups [29±31] have reported that SDIs reduce nerve conduction deficit induced by diabetes.…”

mentioning

confidence: 99%

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study

Obrosova

Fathallah

Lang³

et al. 1999

Diabetologia

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Numerous studies in experimental models of diabetes [1±5] as well as a few clinical trials [6±9] have shown a reduction of peripheral nerve conduction deficit and morphological abnormalities by structurally different aldose reductase inhibitors thus implicating increased activity of the sorbitol pathway in the pathogenesis of diabetic neuropathy. The mechanisms leading from increased sorbitol pathway activity to complex functional, metabolic and morphological changes in the peripheral nervous system in diabetes are not com- Diabetologia (1999) AbstractAims/hypothesis. Studies of the role of sorbitol dehydrogenase in nerve functional deficits induced by diabetes reported contradictory results. We evaluated whether sorbitol dehydrogenase inhibition reduces metabolic abnormalities and enhances oxidative stress characteristic of experimental diabetic neuropathy. Methods. Control and streptozotocin-diabetic rats were treated with or without sorbitol dehydrogenase inhibitor (SDI)-157 (100 mg × kg ±1 × day ±1 , in the drinking water, for 3 weeks). Sciatic nerve free mitochondrial (cristae and matrix) and cytosolic NAD + : NADH ratios were calculated from the b-hydroxybutyrate, glutamate and lactate dehydrogenase systems. Concentrations of metabolites, e. g. sorbitol pathway intermediates and variables of energy state were measured in individual nerves spectrofluorometrically by enzymatic procedures. Results. The flux through sorbitol dehydrogenase (manifested by nerve fructose concentrations) was inhibited by 53 % and 74 % in control and diabetic rats treated with SDI compared with untreated control and diabetic groups. Free NAD + :NADH ratios in mitochondrial cristae, matrix and cytosol were decreased in diabetic rats compared with controls and reduction in either of the three variables was not prevented by sorbitol dehydrogenase inhibitor. Phosphocreatine concentrations and phosphocreatine:creatine ratios were decreased in diabetic rats compared with controls and were further reduced by the inhibitor. Malondialdehyde plus 4-hydroxyalkenals concentration was increased and reduced gluthathione concentration was reduced in diabetic rats compared with the control group, and changes in both variables were further exacerbated by sorbitol dehydrogenase inhibitor. Neither NAD-redox and energy states nor lipid aldehyde and reduced gluthathione concentrations were affected by treatment with the inhibitor in control rats. Conclusion/interpretation. Inhibition of sorbitol dehydrogenase does not offer an effective approach for prevention of oxidation and metabolic imbalances in the peripheral nerve that is induced by diabetes and is adverse rather than beneficial. [Diabetologia (1999

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Effects of sorbitol dehydrogenase deficiency on nerve conduction in experimental diabetic mice.

Cited by 65 publications

References 0 publications

Deletion of Aldose Reductase Leads to Protection against Cerebral Ischemic Injury

Deletion of Aldose Reductase Leads to Protection against Cerebral Ischemic Injury

Schwann cell interactions with axons and microvessels in diabetic neuropathy

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study

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