Increased Axonal Regeneration and Swellings in Intraepidermal Nerve Fibers Characterize Painful Phenotypes of Diabetic Neuropathy

Cheng, Hong; Dauch, Jacqueline R.; Porzio, Michael T.; Yanik, Brandon M.; Hsieh, Wilson; Smith, A. Gordon; Singleton, J. Robinson; Feldman, Eva L.

doi:10.1016/j.jpain.2013.03.005

Cited by 95 publications

(94 citation statements)

References 23 publications

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“…It is possible that our observed larger mitochondrial signals could be composed of clusters of smaller, potentially dysfunctional mitochondria that have gone through aberrant fission, or of larger predegenerative, swollen mitochondria 40–43. In support of this, recent work from our group observed axonal swelling associated with IENFs of patients with diabetic neuropathic pain 44. It is possible that mitochondrial and axonal swellings are associated with changes in sensory nerve function.…”

Section: Discussionsupporting

confidence: 68%

Hyperglycemia‐ and neuropathy‐induced changes in mitochondria within sensory nerves

Hamid

Mervak

Münch

et al. 2014

Ann Clin Transl Neurol

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ObjectiveThis study focused on altered mitochondrial dynamics as a potential mechanism for diabetic peripheral neuropathy (DPN). We employed both an in vitro sensory neuron model and an in situ analysis of human intraepidermal nerve fibers (IENFs) from cutaneous biopsies to measure alterations in the size distribution of mitochondria as a result of hyperglycemia and diabetes, respectively.MethodsNeurite- and nerve-specific mitochondrial signals within cultured rodent sensory neurons and human IENFs were measured by employing a three-dimensional visualization and quantification technique. Skin biopsies from distal thigh (DT) and distal leg (DL) were analyzed from three groups of patients; patients with diabetes and no DPN, patients with diabetes and confirmed DPN, and healthy controls.ResultsThis analysis demonstrated an increase in mitochondria distributed within the neurites of cultured sensory neurons exposed to hyperglycemic conditions. Similar changes were observed within IENFs of the DT in DPN patients compared to controls. This change was represented by a significant shift in the size frequency distribution of mitochondria toward larger mitochondria volumes within DT nerves of DPN patients. There was a length-dependent difference in mitochondria within IENFs. Distal leg IENFs from control patients had a significant shift toward larger volumes of mitochondrial signal compared to DT IENFs.InterpretationThe results of this study support the hypothesis that altered mitochondrial dynamics may contribute to DPN pathogenesis. Future studies will examine the potential mechanisms that are responsible for mitochondrial changes within IENFs and its effect on DPN pathogenesis.

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Section: Discussionsupporting

confidence: 68%

Hyperglycemia‐ and neuropathy‐induced changes in mitochondria within sensory nerves

Hamid

Mervak

Münch

et al. 2014

Ann Clin Transl Neurol

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“…The main symptoms of diabetic neuropathy are tingling and numbness in the distal extremities sometimes accompanied by burning pain (Argoff et al 2006). Animal and human histochemical studies indicate that diabetes can cause dieback of PNS epidermal endings (Sorensen et al 2006; Cheng et al 2013; Cheung et al 2015; Ebenezer and Polydefkis 2014), an outcome that may not be related to pain (Sorensen et al 2006). Also, in studies where diabetes is modeled in animals, the development of ectopic activity in DRG neurons (Khan et al 2002; Serra et al 2012) has been demonstrated.…”

Section: 8 Ampk: Diabetic Neuropathy Prevention and Treatmentmentioning

confidence: 99%

Targeting AMPK for the Alleviation of Pathological Pain

Asiedu

Dussor

Price

2016

Experientia Supplementum

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Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.

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“…Upregulation of receptor over time in painful DPN (Pabbidi et al, 2008) Altered ion-channel expression or function Upregulation of expression of voltage gated Na channels 1.3, 1.6, 1.9 Dysregulation of expression of Na channel 1.8 (Craner et al, 2002) Post-translational modification of Na (v) 1.8 by methylglyoxal causing increased excitability (Bierhaus et al, 2012) Upregulation Ca channels, and dysregulation of cellular calcium leading to increased excitability Decreased fiber counts in painful DPN, increased regenerative markers (Quattrini et al, 2007;Cheng et al, 2013) BDNF, brain-derived neurotrophic factor; Ca, calcium; IENFD, intraepidermal nerve fiber density; NGF, nerve growth factor; PDPN, painful diabetic peripheral neuropathy; PLDPN, painless diabetic peripheral neuropathy; STZ, streptozotocin; TRPV1, transient receptor potential cation channel subfamily V member 1.…”

Section: Trpv1mentioning

confidence: 99%