The role of TNF-alpha/NF-kappa B pathway on the up-regulation of voltage-gated sodium channel Nav1.7 in DRG neurons of rats with diabetic neuropathy
The role of TNF-alpha/NF-kappa B pathway on the up-regulation of voltage-gated sodium channel Nav1.7 in DRG neurons of rats with diabetic neuropathy
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DOI：
10.1016/j.neuint.2014.05.012
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发表时间：
2014-09-01
影响因子：
4.2
通讯作者：
Zhong, Yi
中科院分区：
文献类型：
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作者：
Huang, Yangliang;Zang, Ying;Zhong, Yi
糖尿病性神经病变（DN）是周围神经病变的一种常见形式，但这种疾病引起慢性疼痛的机制尚不清楚。电压门控钠通道Nav1.7的表达和功能上调与DN有关，但其确切机制尚不清楚。在本研究中，我们发现部分链脲佐菌素（STZ）治疗的大鼠出现了长时间的机械异常性疼痛和热痛觉过敏。DN大鼠脊髓背根神经节（DRG）中Nav1.7表达上调，双免疫荧光染色显示Nav1.7表达上调与大、小神经元共定位，不与卫星胶质细胞共定位。沙利度胺抑制肿瘤坏死因子- α (tnf - α)的合成可抑制DN，同时强烈阻断DRG中Nav1.7、tnf - α和p-核因子- κ B （p- nf - κ B）的上调。鞘内注射NF-kappa B抑制剂吡咯烷二硫代氨基甲酸酯（PDTC）可显著减轻DRG神经元的疼痛行为和Nav1.7的过表达。这些数据提示，tnf - α升高可能是DN大鼠DRG神经元中Nav1.7上调的原因，而nf - κ B信号通路参与了这一过程。这一发现可能为预防糖尿病性神经病变提供潜在靶点。(C) 2014 Elsevier Ltd.版权所有。
Diabetic neuropathy (DN) is a common form of peripheral neuropathy, yet the mechanisms responsible for chronic pain in this disease are poorly understood. The up-regulation of the expression and function of voltage-gated sodium channel Nav1.7 has been implicated in DN, however, the exact mechanism is unclear. In the present study, we found that a proportion of streptozotocin (STZ)-treated rats suffered from mechanical allodynia and thermal hyperalgesia for a long-lasting time. Nav1.7 was up-regulated in spinal dorsal root ganglia (DRG) of rats with DN, double immunofluorescence staining showed that the increased Nav1.7 was co-localized with large and small sized neurons but not satellite glial cells. Inhibiting the synthesis of tumor necrosis factor-alpha (TNF-alpha) by thalidomide prevented DN, accompanied by strongly blocking the up-regulation of Nav1.7, TNF-alpha and p-nucleus factor-kappa B (p-NF-kappa B) in DRG. Intrathecal injection of NF-kappa B inhibitor pyrrolidine dithiocarbamate (PDTC) significantly attenuated the pain behaviors and over-expression of Nav1.7 in DRG neurons. These data suggest that increased TNF-alpha may be responsible for up-regulation of Nav1.7 in DRG neurons of rats with DN, and NF-kappa B signal pathway is involved in this process. The findings might provide potential target for preventing diabetic neuropathy. (C) 2014 Elsevier Ltd. All rights reserved.