Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Hum Gene Ther. 2009 Jul;20(7):715-27. doi: 10.1089/hum.2009.002.
Deprivation of neurotrophic factors contributes to the pathogenesis of diabetic neuropathy. However, the role of glial cell-derived neurotrophic factor (GDNF) in the pathogenesis of diabetic neuropathy remains unclear. The present study evaluated the pathogenic role of GDNF deficiency and the therapeutic potential of GDNF gene transfer for diabetic neuropathy. After injection of streptozotocin (STZ) for 2 weeks, diabetic rats displayed significant alteration in electrophysiological parameters, which was associated with structural changes and defective myelination in the sciatic nerves. The early diabetic neuropathy was accompanied by attenuation of the GDNF/GFRalpha1/Akt signaling cascade and depletion of sensory neuropeptides in the peripheral nerves. After detection of neuropathy, intramuscular GDNF gene transfer reversed the deficiency of GDNF/Akt signaling in the sciatic nerve and improved the neurological functions of diabetic rats. Moreover, GDNF gene delivery alleviated the axonal demyelination and restored the sensory neuropeptide levels in the sciatic nerve of diabetic rats. In summary, peripheral GDNF gene delivery ameliorates the diabetes-induced downregulation of the GDNF signaling complex in the peripheral nervous system and holds promises for treatment of diabetic neuropathy.
神经营养因子剥夺导致糖尿病性神经病发病机制。然而，胶质细胞衍生的神经营养因子（GDNF）在糖尿病性神经病发病机制中的作用仍不清楚。本研究评估了 GDNF 缺乏的发病作用和 GDNF 基因转移治疗糖尿病性神经病的潜力。STZ 注射 2 周后，糖尿病大鼠表现出电生理参数的显著改变，这与坐骨神经中的结构改变和髓鞘形成缺陷有关。早期糖尿病性神经病伴随着 GDNF/GFRalpha1/Akt 信号级联的衰减和外周神经中感觉神经肽的耗竭。在检测到神经病后，肌肉内 GDNF 基因转移逆转了坐骨神经中 GDNF/Akt 信号的不足，并改善了糖尿病大鼠的神经功能。此外，GDNF 基因传递减轻了糖尿病大鼠坐骨神经中的轴突脱髓鞘，并恢复了感觉神经肽水平。总之，外周 GDNF 基因传递改善了糖尿病引起的外周神经系统中 GDNF 信号复合物的下调，并为治疗糖尿病性神经病提供了希望。
