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      Gender differences in nerve regeneration after sciatic nerve injury and repair in healthy and in type 2 diabetic Goto-Kakizaki rats

      research-article
      ,
      BMC Neuroscience
      BioMed Central
      Nerve regeneration, Nerve repair, Neuropathy, Diabetes, Gender differences, Schwann cells

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          Abstract

          Background

          In view of the global increase in diabetes, and the fact that recent findings indicate that diabetic neuropathy is more frequently seen in males, it is crucial to evaluate any gender differences in nerve regeneration in diabetes. Our aim was to evaluate in short-term experiments gender dissimilarities in axonal outgrowth in healthy and in genetically developed type 2 diabetic Goto-Kakizaki (GK) rats, and also to investigate the connection between activated (i.e. ATF-3, Activating Transcription Factor 3) and apoptotic (cleaved caspase 3) Schwann cells after sciatic nerve injury and repair. Female and male diabetic GK rats, spontaneously developing type 2 diabetes, were compared with corresponding healthy Wistar rats. The sciatic nerve was transected and instantly repaired. After six days the nerve was harvested to measure axonal outgrowth (i.e. neurofilament staining), and to quantify the number of ATF-3 (i.e. activated) and cleaved caspase 3 (i.e. apoptotic) stained Schwann cells using immunohistochemistry.

          Results

          Axonal outgrowth was generally longer in male than in female rats and also longer in healthy than in diabetic rats. Differences were observed in the number of activated Schwann cells both in the distal nerve segment and close to the lesion site. In particular the female diabetic rats had a lower number. There were no gender differences in number of cleaved caspase 3 stained Schwann cells, but rats with diabetes exhibited more (such cleaved caspase 3 stained Schwann) cells both at the lesion site and in the distal part of the sciatic nerve. Axonal outgrowth correlated with the number of ATF3 stained Schwann cells, but not with blood glucose levels or the cleaved caspase 3 stained Schwann cells. However, the number of cleaved caspase 3 stained Schwann cells correlated with the blood glucose level.

          Conclusions

          We conclude that there are gender differences in nerve regeneration in healthy rats and in type 2 diabetic GK rats.

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          Most cited references50

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          Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury.

          Activating transcription factor 3 (ATF3), a member of ATF/CREB family of transcription factors, is induced in a variety of stressed tissue. ATF3 regulates transcription by binding to DNA sites as a homodimer or heterodimer with Jun proteins. The purpose of this study was to examine the expression and regulation of ATF3 after axonal injury in neurons in dorsal root ganglia (DRG) and spinal cord. In naive rats, ATF3 was not expressed in the DRG and spinal cord. Following the cut of peripheral nerve, ATF3 was immediately induced in virtually all DRG neurons and motoneurons that were axotomized, and the time course of induction was dependent on the distance between the injury site and the cell body. Double labeling using immunohistochemistry revealed that the population of DRG neurons expressing ATF3 included those expressing c-jun, and in motoneurons ATF3 and c-jun were concurrently expressed after axotomy. In contrast to c-jun, ATF3 was not induced transsynaptically in spinal dorsal horn neurons. We conclude that ATF3 is specifically induced in sensory and motoneurons in the spinal cord following nerve injury and should be regarded as an unique neuronal marker of nerve injury in the nervous system. Copyright 2000 Academic Press.
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            Neurons undergo apoptosis in animal and cell culture models of diabetes.

            Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed. In addition mitochondrial changes recently reported to occur as part of the apoptotic cascade, such as ballooning of mitochondria and disruption of the internal cristae, are seen in diabetic dorsal root ganglion neurons and Schwann cells. Similar changes have been reported in neurons in the presence of oxidative stress. In order to study the neurotoxic effects of high glucose we developed an in vitro model using rat dorsal root ganglion neurons. In dorsal root ganglion cultured in defined medium, addition of moderate glucose levels results in neurite degeneration and apoptosis. These changes are coupled with activation of caspase-3, dependent on the concentration of glucose. The apoptotic changes observed in vitro are similar to those observed in vivo. In contrast, addition of IGF-I, even at physiological concentrations, prevents activation of caspase-3 and neuronal apoptosis in vitro. We suggest that oxidative stress may promote the mitochondrial changes in diabetic animals and lead to activation of programmed cell death caspase pathways. These results imply a new pathogenetic mechanism for diabetic sensory neuropathy. Copyright 1999 Academic Press.
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              Oxidative stress and programmed cell death in diabetic neuropathy.

              Recent evidence in both animal models and human sural nerve biopsies indicates an association with oxidative stress, mitochondrial (Mt) membrane depolarization (MMD), and induction of programmed cell death (PCD). In streptozotocin (STZ)-treated diabetic rats, hyperglycemia induces typical apoptotic changes as well as swelling and disruption of the Mt cristae in diabetic dorsal root ganglion neurons (DRG) and Schwann cells (SC), but these changes are only rarely observed in control neurons. In human sural nerve biopsies, from patients with diabetic sensory neuropathy, there is transmission electromicrograph evidence of swelling and disruption of the Mt and cristae compared to patients without peripheral neuropathy. In human SH-SY5Y neurons, rat sensory neurons, and SC, in vivo, there is an increase in reactive oxygen species (ROS) after exposure to 20 mM added glucose. In parallel, there is an initial Mt membrane hyperpolarization followed by depolarization (MMD). In turn, MMD is coupled with cleavage of caspases. Various strategies aimed at inhibiting the oxidative burst, or stabilizing the DeltaPsi(M), block induction of PCD. First, growth factors such as NGF can block induction of ROS and/or stabilize the DeltaPsi(M). This, in turn, is associated with inhibition of PCD. Second, reduction of ROS generation in neuronal Mt prevents neuronal PCD. Third, up-regulation of uncoupling proteins (UCPs), which stabilize the DeltaPsi(M), blocks induction of caspase cleavage. Collectively, these findings indicate that hyperglycemic conditions observed in diabetes mellitus are associated with oxidative stress-induced neuronal and SC death, and targeted therapies aimed at regulating ROS may prove effective in therapy of diabetic neuropathy.
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                Author and article information

                Contributors
                Lena.Stenberg@med.lu.se
                Lars.Dahlin@med.lu.se
                Journal
                BMC Neurosci
                BMC Neurosci
                BMC Neuroscience
                BioMed Central (London )
                1471-2202
                13 September 2014
                13 September 2014
                2014
                : 15
                : 1
                : 107
                Affiliations
                Department of Clinical Sciences - Hand Surgery, Lund University, Skane University Hospital, Malmö, Sweden
                Article
                3796
                10.1186/1471-2202-15-107
                4169809
                25216784
                6e7f5232-d798-4717-9ea8-6544d3edc6da
                © Stenberg and Dahlin; licensee BioMed Central Ltd. 2014

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 3 April 2014
                : 9 September 2014
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2014

                Neurosciences
                nerve regeneration,nerve repair,neuropathy,diabetes,gender differences,schwann cells
                Neurosciences
                nerve regeneration, nerve repair, neuropathy, diabetes, gender differences, schwann cells

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