Kato Naoki, Nemoto Koichi, Nakanishi Kuniaki, Morishita Ryuichi, Kaneda Yasufumi, Uenoyama Maki, Ikeda Tomosumi, Fujikawa Kyosuke
Department of Orthopaedic Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, Japan 359-8513.
Diabetes. 2005 Mar;54(3):846-54. doi: 10.2337/diabetes.54.3.846.
Peripheral neuropathy is common and ultimately accounts for significant morbidity in diabetes. Recently, several neurotrophic factors have been used to prevent progression of diabetic neuropathy. In this study, we gave repeated intramuscular injections of the human hepatocyte growth factor (HGF) gene percutaneously, using liposomes containing the hemagglutinating virus of Japan (HVJ), to examine therapeutic efficacy of nonviral gene transfer of HGF for experimental diabetic sensorimotor neuropathy in rats. Experimental diabetes induced by intraperitoneal injection of streptozotocin resulted in a marked tactile allodynia (but not in a thermal hyperalgesia), in a reduction of both the conduction velocity and the amplitude, and in a decreased laser Doppler flux of the nerve and the muscle at 6 weeks after the induction. All these changes were significantly reversed by repeated gene transfer of HGF. Furthermore, we analyzed the density of endoneurial capillaries and morphometrical changes of the nerve. The density of endoneurial capillaries, disclosing marked reduction in diabetic rats, was also reversed significantly by repeated gene transfer of HGF; however, no considerable differences were observed morphometrically in either myelinated or unmyelinated axons. These results suggest that nonviral HVJ liposome-mediated gene transfer of human HGF has potential for the safe effective treatment of diabetic sensorimotor neuropathy.
周围神经病变在糖尿病中很常见，最终会导致严重的发病率。最近，几种神经营养因子已被用于预防糖尿病神经病变的进展。在本研究中，我们使用含有日本血凝病毒（HVJ）的脂质体经皮反复肌肉注射人肝细胞生长因子（HGF）基因，以研究HGF非病毒基因转移对大鼠实验性糖尿病感觉运动神经病变的治疗效果。腹腔注射链脲佐菌素诱导的实验性糖尿病在诱导后6周导致明显的触觉异常性疼痛（但无热痛觉过敏）、传导速度和振幅降低，以及神经和肌肉的激光多普勒血流减少。HGF的反复基因转移显著逆转了所有这些变化。此外，我们分析了神经内膜毛细血管的密度和神经的形态学变化。糖尿病大鼠神经内膜毛细血管密度明显降低，HGF的反复基因转移也使其显著逆转；然而，在有髓或无髓轴突的形态学上未观察到明显差异。这些结果表明，非病毒HVJ脂质体介导的人HGF基因转移具有安全有效治疗糖尿病感觉运动神经病变的潜力。
