Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy.

Fernyhough, Paul; Gallagher, Alex; Averill, Sharon; Priestley, John V.; Hounsom, Luke; Patel, Jyoti; Tomlinson, David R.

doi:10.2337/diabetes.48.4.881

Cited by 167 publications

(119 citation statements)

References 50 publications

(83 reference statements)

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“…Complications associated with neurofilament phosphorylation were avoided in this study by choosing an NF-H antibody that is not sensitive to neurofilament phosphorylation. Importantly, NT-3 treatment reduces these deficits, consistent with our findings regarding NT-3 treatment (Mizisin et al, 1999;Fernyhough et al, 1999;Sayers et al, 2003). Interestingly, we also demonstrate that mice treated with NT-3 displayed a significant increase in Merkel cells associated with nerve fibers, suggesting that NT-3 treatment stimulated formation and innervation of sensory receptors de novo.…”

Section: Neurotrophic Modulation Of Mechanical Insensitivity and Myelsupporting

confidence: 91%

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Christianson¹,

Ryals²,

Johnson³

et al. 2007

Neuroscience

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Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to STZ administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to NF-H and MBP. Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pin prick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared to non-diabetic mice. To test whether two neurotrophins NGF and/or NT-3 known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for two weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared to diabetic mice treated with insulin for two weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared to control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophininduced increases in dermal innervation and behavior emphasize the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy. KeywordsNeuropathy; diabetes; dermis; innervation; myelinated axon NGF; NT-3 *Correspondence: Douglas Wright, Ph.D., Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, Phone:913-588-2713, Fax: 913-588-2710, email: dwright@kumc.edu. Section Editor: Donna HammondPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , 1984). The predominant type of diabetic neuropathy is a distal, symmetrical, sensorimotor polyneuropathy and preferentially affects sensory function in the distal regions, i...

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Section: Neurotrophic Modulation Of Mechanical Insensitivity and Myelsupporting

confidence: 91%

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Christianson¹,

Ryals²,

Johnson³

et al. 2007

Neuroscience

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“…2). Dorsal root ganglia from rats with streptozotocin-induced diabetes show strong steady-sate activation of both ERK and JNK ( [96] and Fig. 2).…”

Section: Oxidative Stressmentioning

confidence: 99%

“…The consequences of persistent activation of MAP kinases in diabetes are also unknown as yet, though some speculations are possible. Firstly, the consequences possibly differentiate between different classes of neurone, because ERK is strikingly absent from the cell bodies of motor neurones [96]. Accordingly an involvement in dysfunction could explain the predisposition of diabetic neuropathy for sensory fibres.…”

Section: Diabetic Neuropathymentioning

confidence: 99%

“…There is good evidence that the persistent activation of JNK causes phosphorylation of inappropriate substrates, in particular non-nuclear substrates such as neurofilaments, where it could be the direct cause of hyperphosphorylation [96]. Hyperphosphorylation of neurofilaments is associated with filamentous tangles, axodendritic swell-ing and neurodegeneration associated and is present in a range of diseases, including human diabetic neuropathy [139,140].…”

Section: Diabetic Neuropathymentioning

confidence: 99%

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Mitogen-activated protein kinases as glucose transducers for diabetic complications

1999

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The results of the Diabetes Control and Complications Trial [1] emphatically confirmed the heroic studies of Jean Pirart [2±4], showing that poor control of glycaemia in Type I (insulin-dependent) diabetes mellitus predisposes patients to chronic complications. This has led to the tacit assumption that glucose, at supranormal concentrations, is the agent of damage. Participation of hypoinsulinaemia or other manifestations of poor control cannot be discounted but glucose itself certainly has the capacity to disturb biosystems. It can do this in a variety of ways, so that hypotheses to explain specific complications ± retinopathy, nephropathy and neuropathy ± starting from high glucose are tenable, testable and, therefore, useful.Figure 1 presents a simple generic plan by which complications develop. It usefully discriminates between metabolic effects of glucose on the target cells showing the complication and the exacerbating effect of independent accelerators, such as arterial hypertension in diabetic nephropathy. Not all independent accelerators have, however, as clearly defined a rela- Diabetologia (1999) AbstractThe damaging effects of glucose on the cells which contribute to the development of diabetic complications are ill-understood. There are three major hypotheses ± the sorbitol pathway, non-enzymatic glycation of proteins and increased oxidative stress ± and many examples illustrate inter-connections between the three. It is suggested that these pathways, together with other biochemical anomalies arising from hyperglycaemia, can synergise by sharing the capacity to activate mitogen-activated protein kinases (MAP kinases) and that these enzymes in actual fact form glucose transducers. The more recent hypothesis, namely that activation of a specific isoform of protein kinase C (PKC) underpin damaging changes in retinopathy and neuropathy, can also be related because protein kinase C is an effective activator of mitogen-activated protein kinases. These latter kinases phosphorylate transcription factors, which in turn alter the balance of gene expression. In this way they can alter cellular phenotype, promote division or increase production of extracellular material. In short, mitogen-activated protein kinases have the capacity to trigger all the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy and it is suggested that their pharmacological modulation might provide therapeutic control of these conditions. [Diabetologia (1999

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“…Metabolic changes in nerve vasculature, with resulting decrease in nerve blood flow and endoneurial hypoxia, have a key role in nerve conduction slowing in short-term diabetes [4, 15±20]. Metabolic imbalances in the neural tissues, closely associated with impaired neurotrophism [13, 25±27, 33] and neurotransmission [34±36], contribute to Schwann cell injury [37,38] and axonopathy [39,40]. These abnormalities which develop gradually and become manifest in long-standing diabetes [38,39] exacerbate nerve functional deficits acquired in the initial phase of diabetic neuropathy.…”

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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Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy.

Cited by 167 publications

References 50 publications

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

Mitogen-activated protein kinases as glucose transducers for diabetic complications

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

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