Human Recombinant Nerve Growth Factor Replaces Deficient Neurotrophic Support in the Diabetic Rat

Fernyhough, Paul; Diemel, Lara T.; Hardy, J. H.; Brewster, Wendy J.; Mohiuddin, Liza; Tomlinson, David R.

doi:10.1111/j.1460-9568.1995.tb01098.x

Cited by 104 publications

(62 citation statements)

References 21 publications

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“…Other factors including neurotrophic factors such as NGF and NT-3 could be involved in the improvement of NCV. In the present study, NGF and NT-3 protein contents were reduced in hind limb muscles of STZ-induced diabetic rats, consistent with previous works that demonstrated the role of these neurotrophines in DPN (43,44). However, MSC transplantation improved NCV without affecting the protein levels of NGF and NT-3 in hind limb muscles of STZ-induced diabetic rats.…”

Section: Discussionsupporting

confidence: 81%

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

et al. 2008

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OBJECTIVE-Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats.RESEARCH DESIGN AND METHODS-MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number-to-muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated.RESULTS-VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number-to-muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation. D iabetic polyneuropathy (DPN) is the most common complication of diabetes. It is estimated that ϳ20 -30% of diabetic patients are affected by symptomatic DPN (1). Generally, DPN develops symmetrically in a length-dependent fashion, with dying back or dropout of the longest nerve fibers; both myelinated and unmyelinated, large and small are affected. Diabetic patients suffer from various symptoms of DPN, such as spontaneous pain, hyperalgesia, and diminished sensation (2). It has been shown that tight glycemic control is effective in slowing the progression of DPN but cannot completely prevent it (3). Therefore, additional therapeutic strategies are required. CONCLUSIONS-TheseNeural cell degeneration and decreased nerve blood flow (NBF) have been recognized as pathophysiologically characteristic features of DPN (4). Therefore, therapeutic agents that could act as both neurotrophic and angiogenic factors would be useful for the treatment of DPN even at an advanced stage. We previously demonstrated that local administration of basic fibroblast growth factor (bFGF) by intramusclar injection with crosslinked gelatin hydrogel improved the impaired nerve functions of streptozotocin (STZ)-induced diabetic rats, including amelioration of decreased NBF, hypoalgesia, and the delayed motor nerve conduction velocity (MNCV) on the treated side of sciatictibial nerves and that these effects were maintained for at least 30 days (5). Schratzberger et al. (6) showed that vascular endothelial growth factor (VEGF) gene transfer significantly increased the NCV and NBF as well as the vascular densities in muscle and peripheral nerv...

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Section: Discussionsupporting

confidence: 81%

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

et al. 2008

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“…This is speculative, but some conflict is certainly possible and part of the signalling process for NGF requires its capture, internalisation and retrograde axonal transport to the neuronal cell body, processes which are impaired in diabetes [133,134]. It is impossible to reconcile the reduced concentrations of NGF available to peripheral neurones in diabetic rats [135] and the impaired receptor function [136,137] with any assumption that ERK is activated only as part of the NGF signalling cascade. Clearly, in diabetic rats, ERK activation in neurones is driven by something other than neurotrophins; but it is not driven by insulin, which, along with NGF, was the first physiological ERK activator to be identified [138].…”

Section: Diabetic Neuropathymentioning

confidence: 89%

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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“…25 Particular examples of critical processes that may be impaired by altered axon transport include mitochondrial transport and dynamics that are critical for energy homeostasis within neurons and their axons, 26 and abnormalities in growth factor signaling, which depends on intact retrograde axon transport to provide the mechanism for target-tissueederived growth factors to signal to the neuron nucleus far away from target tissues. 27,28 Axon TransporteMediated PN Although axon transport can be impaired as a consequence of deranged metabolism in systemic diseases such as DM or by toxic substances that target elements of the intracellular transport machinery, such as chemotherapeutic agents, there are many examples of inherited neuropathy caused by genetic mutations that are associated with some form of aberrant axon transport. Studies focused on understanding how gene mutations alter the function of encoded proteins have provided insight into potential molecular targets for therapy.…”

Section: Axon Transport and Its Role In Neuron And Axon Homeostasismentioning

confidence: 99%

Axon Transport and Neuropathy

Tourtellotte

2016

The American Journal of Pathology

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Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. (Am J Pathol 2016, 186: 489e499; http://dx

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Human Recombinant Nerve Growth Factor Replaces Deficient Neurotrophic Support in the Diabetic Rat

Cited by 104 publications

References 21 publications

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Axon Transport and Neuropathy

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