Ciliary Neurotrophic Factor Improves Nerve Conduction and Ameliorates Regeneration Deficits in Diabetic Rats

Mizisin, Andrew P.; Vu, Yvonne; Shuff, Michelle; Calcutt, Nigel A.

doi:10.2337/diabetes.53.7.1807

Cited by 67 publications

(43 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A variety of mechanisms have been implicated in the pathogenesis of PDN, including increased aldose reductase activity (19 -21), nonenzymatic glycation/glycoxidation (18,22,23), activation of protein kinase C (24), impaired neurotrophic support (25,26), and enhanced oxidative-nitrosative stress (9 -13,27) and, recently, downstream effectors of free radical and oxidant-induced injury, i.e., mitogen-activated protein kinase (MAPK) activation (28), PARP activation (3,8), and impaired calcium signaling (29). All of these mechanisms have been demonstrated to contribute to early PDN and to cause motor and sensory nerve conduction deficits, neurovascular dysfunction, altered sensation, and diabetic neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy

Drel

Szabó

et al. 2005

Diabetes

View full text Add to dashboard Cite

Poly(ADP-ribose) polymerase (PARP) inhibition has recently been identified as a novel approach to treatment of experimental peripheral diabetic neuropathy (PDN). (5); 2) changes in transcriptional regulation and gene expression (5-7); and 3) poly-(ADP-ribosyl)ation and resulting inhibition of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase, with concomitant activation of several major pathogenetic mechanisms, i.e., nonenzymatic glycation, protein kinase C, and hexosamine pathway (2). Using a pharmacological approach with several structurally unrelated PARP inhibitors as well as PARP-deficient mice, we have recently discovered the key role of PARP in the development of early peripheral diabetic neuropathy (PDN) (3,8). Note that PARP inhibitors administered in doses resulting in complete or almost complete PARP inhibition in the diabetic peripheral nerve (3,8) appeared at least 100-fold more effective in correcting nerve conduction slowing, NAD ϩ /NADH redox imbalances, energy failure, and neurovascular dysfunction than conventional antioxidants (9,10).A recent 9-month PARP inhibitor study in the streptozotocin (STZ)-induced diabetic rat model did not reveal clearly manifest side effects (4), and PARP Ϫ/Ϫ mice do not develop obvious phenotypic changes (5). However, the long-term consequences of complete PARP inhibition in pathological conditions associated with oxidative stress, including diabetes, are unclear and can hardly be sorted out in rodents because of their limited life span. Diabetesassociated oxidative stress leads to DNA damage, e.g., in the peripheral nervous system (11), and PARP activation is an important mechanism of DNA repair (5). Therefore, it is reasonable to suggest that 1) complete PARP inhibition can potentially result in premature aging and 2) targeted delivery of PARP-1 antisense oligodeoxynucleotide-containing vectors (12) or PARP-1 RNA interference (RNAi) (13), rather than pharmacological PARP inhibition, should be considered as a future therapy of PDN (1). However, it is unlikely that such approaches will be available in clinical practice in the near future. An alternative strategy would be to develop low-dose PARP inhibitor-containing combination therapies with other agents already used in clinical practice and proven to be effective in the treatment

show abstract

Section: Discussionmentioning

confidence: 99%

Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy

Drel

Szabó

et al. 2005

Diabetes

View full text Add to dashboard Cite

show abstract

“…Nevertheless, many rodent models of diabetes exhibit indicators of Schwann cell dysfunction, including reduced expression of myelin-associated proteins 47 and Schwann cell-derived trophic factors, such as CNTF 19 and desert hedgehog 20,48 . These perturbations have the potential to affect both neuronal 49 and vascular 48 function, and changes in CNTF expression are prevented by aldose reductase inhibition 50 . In addition, studies in cultured Schwann cells have suggested that increased flux through the polyol pathway drives Schwann cells towards an immature phenotype 51 .…”

Section: Polyneuropathy Mononeuropathiesmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…Electrophysiological parameters were determined as previously described in multiple papers (84,85). Animals were anesthetized with isoflurane and stimulating electrodes placed at the sciatic notch and Achilles tendon of the left hind limb, with recording electrodes placed in the interosseus muscles of the ipsilateral foot.…”

Section: Methodsmentioning

confidence: 99%

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Calcutt¹,

Smith²,

Frizzi³

et al. 2017

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

Ciliary Neurotrophic Factor Improves Nerve Conduction and Ameliorates Regeneration Deficits in Diabetic Rats

Cited by 67 publications

References 40 publications

Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy

Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy

Schwann cell interactions with axons and microvessels in diabetic neuropathy

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Contact Info

Product

Resources

About