Quantitation of epidermal nerves in diabetic neuropathy

Kennedy, William R.; Wendelschafer‐Crabb, Gwen; Johnson, T.L.

doi:10.1212/wnl.47.4.1042

Cited by 402 publications

(353 citation statements)

References 16 publications

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“…a lower IENFD than the SOD2 +/+ db/db mice (p < 0.05). The anticipated differences between epidermal nerve fiber densities in diabetic and control animals (regardless of SOD2 expression) were also in accordance with published reports in human patients (Yasuda et al, 1985;Levy et al, 1989;Kennedy et al, 1996;Arezzo, 1999) and experimental models of DN (Christianson et al, 2003).…”

Section: Discussionsupporting

confidence: 90%

“…The foot pad innervation study in the male C57BL/6J SOD2 +/+ and SOD2 +/− mice confirmed that there was no hind paw neuropathy. This anatomical assessment of neuropathy is part of the standard neuropathy phenotyping recommended by the AMDCC (www.amdcc.org) and is sensitive and reproducible (Levy et al, 1989;Kennedy et al, 1996;Arezzo, 1999). The TRAP values suggest that these mice did not develop significant oxidative stress in the DRG, so we may conclude that loss of one copy of SOD2 was not sufficient to increase oxidative stress in vivo, despite our observations in vitro.…”

Section: Discussionmentioning

confidence: 73%

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SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

105

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Hyperglycemia-induced oxidative stress is an inciting event in the development of diabetic complications including diabetic neuropathy. Our observations of significant oxidative stress and morphological abnormalities in mitochondria led us to examine manganese superoxide dismutase (SOD2), the enzyme responsible for mitochondrial detoxification of oxygen radicals. We demonstrate that over expression of SOD2 decreases superoxide (O 2 •− ) in cultured primary dorsal root ganglion (DRG) neurons and subsequently blocks caspase-3 activation and cellular injury. Under expression of SOD2 in dissociated DRG cultures from adult SOD2 +/− mice results in increased levels of O 2 •− , activation of caspase-3 cleavage and decreased neurite outgrowth under basal conditions that are exacerbated by hyperglycemia. These profound changes in sensory neurons led us to explore the effects of decreased SOD2 on the development of diabetic neuropathy (DN) in mice. DN was assessed in SOD2 +/− C57BL/6J mice and their SOD2 +/+ litter mates following streptozotocin (STZ) treatment. These animals, while hyperglycemic, do not display any signs of DN. DN was observed in the C57BL/6Jdb/db mouse, and decreased expression of SOD2 in these animals increased DN. Our data suggest that SOD2 activity is an important cellular modifier of neuronal oxidative defense against hyperglycemic injury.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 73%

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

105

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“…Recent advances in quantitation of epidermal innervation have confirmed that human diabetics have significantly reduced epidermal innervation (McCarthy et al, 1995;Kennedy et al, 1996). Epidermal changes have been correlated with reduced conduction velocity, suggesting that quantitative analysis of cutaneous innervation may be indicative of developing neuropathies (Herrmann et al, 1999;Hirai et al, 2000).…”

mentioning

confidence: 99%

“…Interest in using exogenous neurotrophins to treat diabetic neuropathy in humans has slowed due to the outcomes in clinical trials, but studies in animal models continue to report beneficial effects. Importantly, these studies in rodents point out the diverse actions of neurotrophins on select populations of sensory neurons and that identifying neurotrophin-induced effects require selective and appropriate assessments (reviewed in Apfel, 2002; Lenninger et al, 2004).Recent advances in quantitation of epidermal innervation have confirmed that human diabetics have significantly reduced epidermal innervation (McCarthy et al, 1995;Kennedy et al, 1996). Epidermal changes have been correlated with reduced conduction velocity, suggesting that quantitative analysis of cutaneous innervation may be indicative of developing neuropathies (Herrmann et al, 1999;Hirai et al, 2000).…”

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confidence: 99%

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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“…Biopsies were fixed in Zamboni solution for 24 hours and then cryoprotected. 10,11 Thick, 50-m sections were cut vertical to the skin surface, at 90 o to the fingerprint ridges, processed for indirect immunofluorescence, and MCs were quantified as described. 12 Data analyses.…”

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confidence: 99%

A new device to quantify tactile sensation in neuropathy

Kennedy¹,

Selim²,

Brink³

et al. 2011

Neurology

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Objective: To devise a rapid, sensitive method to quantify tactile threshold of finger pads for early detection and staging of peripheral neuropathy and for use in clinical trials.Methods: Subjects were 166 healthy controls and 103 patients with, or at risk for, peripheral neuropathy. Subjects were screened by questionnaire. The test device, the Bumps, is a checkerboard-like smooth surface with 12 squares; each square encloses 5 colored circles. The subject explores the circles of each square with the index finger pad to locate the one circle containing a small bump. Bumps in different squares have different heights. Detection threshold is defined as the smallest bump height detected. In some subjects, a 3-mm skin biopsy from the tested finger pad was taken to compare density of Meissner corpuscles (MCs) to bump detection thresholds. Results:The mean (ϮSEM) bump detection threshold for control subjects was 3.3 Ϯ 0.10 m.Threshold and test time were age related, older subjects having slightly higher thresholds and using more time. Mean detection threshold of patients with neuropathy (6.2 Ϯ 0.35 m) differed from controls (p Ͻ 0.001). A proposed threshold for identifying impaired sensation had a sensitivity of 71% and specificity of 74%. Detection threshold was higher when MC density was decreased. Conclusions:These preliminary studies suggest that the Bumps test is a rapid, sensitive, inexpensive method to quantify tactile sensation of finger pads. It has potential for early diagnosis of tactile deficiency in subjects suspected of having neuropathy, for staging degree of tactile deficit, and for monitoring change over time. Reduced tactile sensation (numbness) is a common symptom of patients with peripheral neuropathy. A need exists for efficient techniques to diagnose and quantify tactile deficiency early, when treatment has the greatest potential of success. Furthermore, evaluation of therapeutic benefits from advances in molecular biology, genetics, pharmacology, and other sciences will require more precise measurements than are currently available.Meissner corpuscles (MCs) are sensitive organs for touch recognition on glabrous skin of the hands and fingers. Early studies showed lower MC density in older persons 1-3 and in neuropathy. 4 More recently, reduced MC density, distorted MC structure, focal thinning or loss of myelin, and short myelin internodes coupled with decreased sensitivity to touch have been reported. [5][6][7] Functional studies of touch conveyed by cutaneous mechanoreceptors in glabrous skin found that detection of small raised dots (bumps) on a smooth surface using the finger pad was signaled by MCs. 8,9 Based on these studies, we devised a simple device called the Bumps to quantify tactile sensitivity on the finger pads. The Bumps test determines the tactile detection threshold by having the subject rub the finger pad over a smooth surface to locate single, coin-shaped bumps of different heights. Using this device, we found a difference in detection thresholds between control subject...

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Quantitation of epidermal nerves in diabetic neuropathy

Cited by 402 publications

References 16 publications

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

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

A new device to quantify tactile sensation in neuropathy

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