Murakami Tatsufumi, Arai Makiko, Sunada Yoshihide, Nakamura Akihiro
Division of Neurology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan.
J Gene Med. 2006 Jun;8(6):773-81. doi: 10.1002/jgm.893.
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 electro-gene therapy for neuropathy, intramuscular VEGF 164 gene transfer by electroporation was performed to treat sensory neuropathy in diabetic mice.
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 electro-gene 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.
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.
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 endoneurium of the peripheral nerve, and may be useful for treatment for diabetic sensory neuropathy in human subjects.
糖尿病性神经病变是周围神经病变最常见的病因，也是糖尿病的一种严重并发症。血管内皮生长因子（VEGF）可刺激血管生成，并具有神经营养和神经保护活性。为了研究VEGF 164电基因疗法治疗神经病变的效果，通过电穿孔进行肌肉内VEGF 164基因转移，以治疗糖尿病小鼠的感觉神经病变。
利用电穿孔注射VEGF 164质粒，使链脲佐菌素诱导的有痛觉减退的糖尿病小鼠的胫前（TA）肌中VEGF 164过表达。从电基因转移后2周起，每周使用爪压试验测量痛觉阈值。在电基因转移后4周，对TA肌、坐骨神经、肝脏和脾脏进行组织化学检查。
在双侧TA肌进行电基因转移后2周，所有治疗小鼠升高的痛觉阈值均降至正常水平。痛觉减退的改善持续了14周。当将VEGF 164质粒通过电穿孔注射到单侧TA肌中时，不仅在同侧后爪，而且在对侧后爪均观察到痛觉减退的恢复，这表明VEGF在血液中循环。在VEGF 164质粒电穿孔小鼠的坐骨神经中，未发现神经内膜血管数量增加。
这些发现表明，VEGF 164电基因疗法通过外周神经神经内膜血管生成以外的机制，完全恢复了糖尿病小鼠的感觉缺陷，即痛觉减退，可能对人类糖尿病感觉神经病变的治疗有用。
