VEGF 164 gene transfer by electroporation improves diabetic sensory neuropathy in mice
VEGF 164 gene transfer by electroporation improves diabetic sensory neuropathy in mice
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DOI：
10.1002/jgm.893
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发表时间：
2006-06-01
影响因子：
3.5
通讯作者：
Nakamura, Akihiro
中科院分区：
文献类型：
--
作者：
Murakami, Tatsufumi;Arai, Makiko;Nakamura, Akihiro
背景糖尿病神经病变是糖尿病周围神经病变最常见的原因，也是糖尿病的严重并发症。血管内皮生长因子(VEGF)可刺激血管生成，具有神经营养和神经保护作用。为探讨血管内皮生长因子164(VEGF164)电基因治疗糖尿病小鼠感觉神经病变的疗效，采用电穿孔法肌肉注射VEGF164基因治疗糖尿病小鼠感觉神经病变。方法采用电穿孔注射VEGF164基因治疗痛觉减退的糖尿病小鼠胫前肌。从电基因转移后2周开始，每周用爪压试验测量伤害性阈值。结果电基因导入双侧TA肌2周后，所有处理组的伤害性阈值均降至正常水平。痛觉减退的改善持续14周。将VEGF164电穿孔注射到一侧TA肌中，不仅同侧后爪疼痛恢复，对侧也有恢复，提示VEGF164在血液中循环。结论VEGF164电基因治疗可完全恢复糖尿病小鼠的感觉缺陷，即痛觉减退，其机制不同于周围神经内神经细胞的血管生成，可用于糖尿病感觉神经病变的治疗。版权所有(C)2006 John Wiley&Sons，Ltd.
Background Diabetic neuropathy is the most common cause of peripheral neuropathy and a serious complication of diabetes. Vascular endothelial growth factor (VEGF) stimulates angiogenesis and has neurotrophic and neuroprotective activities. To examine the efficiency of VEGF 164 electrogene therapy for neuropathy, intramuscular VEGF 164 gene transfer by electroporation was performed to treat sensory neuropathy in diabetic mice.Methods VEGF 164 was overexpressed in the tibial anterior (TA) muscles of streptozotocin-induced diabetic mice with hypoalgesia, using a VEGF 164 plasmid injection with electroporation. From 2 weeks after electrogene transfer, the nociceptive threshold was measured weekly using the paw-pressure test. The TA muscles, sciatic nerve, liver and spleen were histochemically examined at 4 weeks after electro-gene transfer.Results Two weeks after electro-gene transfer into the bilateral TA muscles, the elevated nociceptive threshold was decreased to a normal level in all treated mice. improvement of the hypoalgesia continued for 14 weeks. When the VEGF 164 plasmid was injected with electroporation into a unilateral TA muscle, recovery from hypoalgesia was observed in not only the ipsilateral hindpaw, but also the contralateral one, suggesting that VEGF circulates in the blood. No increase in the number of endoneurial vessels in the sciatic nerve was found in the VEGF 164 plasmid-electroporated mice.Conclusions These findings suggest that VEGF 164 electro-gene therapy completely recovered the sensory deficits, i.e. hypoalgesia, in the diabetic mice through mechanisms other than angiogenesis in the endoneuriurn of the peripheral nerve, and may be useful for treatment for diabetic sensory neuropathy in human subjects. Copyright (c) 2006 John Wiley & Sons, Ltd.