Moro Kazuhisa, Shiotani Akihiro, Watabe Kazuhiko, Takeda Yasuo, Saito Koichiro, Mori Yuko, Ogawa Kaoru
Department of Otolaryngology-Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 1608582, Japan.
Brain Res. 2006 Mar 3;1076(1):1-8. doi: 10.1016/j.brainres.2005.12.119. Epub 2006 Feb 13.
We have previously shown that neuroprotective effects of an adenoviral glial cell line-derived neurotrophic factor (GDNF) gene transfer on the lesioned adult rat motoneurons in the nucleus ambiguus. In the present study, we examined neuroprotective effects of adenoviral gene transfer of brain-derived neurotrophic factor (BDNF) or/and GDNF to motoneurons in nucleus ambiguus using an adult rat vagal nerve avulsion model. The animals avulsed and inoculated with adenoviral vectors encoding BDNF (AxCAmBDNFME) or/and GDNF (AxCAhGDNF) showed immunolabeling for BDNF or/and GDNF in the nucleus ambiguus on the treated side, respectively, and expression of virus-induced BDNF or/and GDNF mRNA transcripts in the brainstem tissue that contained the nucleus ambiguus of the treated side. The treatment with AxCAhGDNF or AxCAmBDNFME significantly prevented the loss of vagal motoneurons in comparison to the control; the protective effect of AxCAmBDNFME was greater than that of AxCAhGDNF. The combined treatment with AxCAmBDNFME and AxCAhGDNF acted synergistically and significantly larger number of vagal motoneurons was preserved as compared to either AxCAmBDNFME treatment or AxCAhGDNF treatment. The treatment with AxCAmBDNFME or/and AxCAhGDNF after avulsion also suppressed the activity of nitric oxide synthase in lesioned motoneurons in the nucleus ambiguus. These results indicate that adenovirus-mediated BDNF and GDNF gene transfer may prevent the degeneration of motoneurons in humans after either vagal nerve injury or recurrent laryngeal nerve injury.
我们之前已经表明，腺病毒介导的胶质细胞源性神经营养因子（GDNF）基因转移对成年大鼠疑核中受损的运动神经元具有神经保护作用。在本研究中，我们使用成年大鼠迷走神经撕脱模型，研究了腺病毒介导的脑源性神经营养因子（BDNF）或/和GDNF基因转移对疑核运动神经元的神经保护作用。接受编码BDNF（AxCAmBDNFME）或/和GDNF（AxCAhGDNF）的腺病毒载体接种的动物，在治疗侧的疑核中分别显示出BDNF或/和GDNF的免疫标记，并且在含有治疗侧疑核的脑干组织中存在病毒诱导的BDNF或/和GDNF mRNA转录本的表达。与对照组相比，AxCAhGDNF或AxCAmBDNFME治疗显著预防了迷走运动神经元的损失；AxCAmBDNFME的保护作用大于AxCAhGDNF。AxCAmBDNFME和AxCAhGDNF联合治疗具有协同作用，与AxCAmBDNFME治疗或AxCAhGDNF治疗相比，保留的迷走运动神经元数量显著更多。撕脱后用AxCAmBDNFME或/和AxCAhGDNF治疗也抑制了疑核中受损运动神经元的一氧化氮合酶活性。这些结果表明，腺病毒介导的BDNF和GDNF基因转移可能预防人类在迷走神经损伤或喉返神经损伤后运动神经元的退化。
