Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice
Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice
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DOI：
10.1016/j.neuroscience.2006.11.064
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发表时间：
2007-03-02
期刊：
影响因子：
3.3
通讯作者：
Wright, D. E.
中科院分区：
文献类型：
--
作者：
Christianson, J. A.;Ryals, J. M.;Wright, D. E.
人类糖尿病患者经常失去接触和振动感觉，但到目前为止，大多数关于糖尿病引起的感觉神经变性的研究都集中在表皮C纤维上。在这里，我们探讨了糖尿病对皮肤有髓纤维的影响与糖尿病小鼠对触觉刺激的行为反应的关系。每周一次的行为学检查在注射链脲佐菌素(STZ)前开始，持续到8周，用抗神经丝重链(NF-H)和髓鞘碱性蛋白(MBP)的抗血清进行免疫组织化学方法观察足底有髓纤维的分布情况。糖尿病小鼠对非有害刺激(单丝)和有害刺激(针刺)的行为反应减弱。此外，与非糖尿病小鼠相比，糖尿病小鼠真皮足垫的神经营养因子-H阳性有髓神经支配减少了50%。为了测试两种已知支持有髓皮肤纤维的神经营养因子(NGF)和/或神经营养因子-3(NT-3)是否会影响有髓神经支配，糖尿病小鼠被鞘内注射NGF、NT-3、NGF和NT-3 2周。然后将接受神经营养因子治疗的小鼠与接受胰岛素治疗2周的糖尿病小鼠进行比较。NGF和胰岛素治疗都增加了糖尿病小鼠对机械刺激的缩爪反应，而NT-3或NGF和NT-3的组合未能改变缩足反应。令人惊讶的是，与对照组相比，所有治疗方法都显著增加了糖尿病小鼠的有髓神经支配，表明高血糖损伤的有髓皮肤纤维对鞘内注射神经营养素有反应。此外，NT-3处理增加了与神经纤维相关的表皮Merkel细胞数量，这与NT-3反应缓慢适应A纤维的数量增加一致。这些研究表明，在糖尿病神经病变中，有髓纤维丢失可能与无髓鞘表皮丢失一样重要，神经营养素诱导的真皮神经支配增加与行为之间的矛盾强调了多种方法的必要性，以准确评估糖尿病神经病变的感觉改善。(C)2006年IBRO。爱思唯尔有限公司出版。保留所有权利。
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 streptozotocin (STZ) administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to neurofilament heavy chain (NF-H) and myelin basic protein (MBP). Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pinprick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared with non-diabetic mice. To test whether two neurotrophins nerve growth factor (NGF) and/or neurotrophin-3 (NT-3) known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for 2 weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared with diabetic mice treated with insulin for 2 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 with 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 neurotrophin-induced increases in dermal innervation and behavior emphasizes the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.