Yan Q, Wang J, Matheson C R, Urich J L
Department of Neuroscience, Amgen, Inc., Thousand Oaks, California 91320, USA.
J Neurobiol. 1999 Feb 15;38(3):382-90. doi: 10.1002/(sici)1097-4695(19990215)38:3<382::aid-neu7>3.0.co;2-5.
Adult rat retinal ganglion cells (RGC) undergo degeneration after optic nerve transection. Studies have shown that exogenously applied neurotrophic factors such as brain-derived neurotrophic factor (BDNF) can attenuate axotomy-induced as well as developmental RGC death. Here, we examined whether glial cell line-derived neurotrophic factor (GDNF), a known neurotrophic factor for dopaminergic neurons and motor neurons, could provide neurotrophic support to RGC in adult rats. We determined whether RGC could retrogradely transport GDNF from their target tissue. After injection into the superior colliculus of adult rats, 125I-GDNF was retrogradely transported to contralateral eyes but not to ipsilateral eyes. The transport of 125I-GDNF could be blocked by coinjection of excess unlabeled GDNF, indicating that it was receptor mediated. We tested whether intravitreally applied GDNF could prevent axotomy-induced RGC degeneration. The RGC were prelabeled with Fluorogold (FG) and axotomized by intraorbital optic nerve transection. GDNF, BDNF (positive control), cytochrome c (negative control), or a GDNF/BDNF combination was injected intravitreally on days 0 and 7. On day 14, FG-labeled RGC were counted from whole-mount retinas. We found that, similar to BDNF, GDNF could significantly attenuate the degeneration of RGC in a dose-dependent fashion. Furthermore, the combination treatment of GDNF and BDNF showed better protection than either factor used individually. Our data indicate that GDNF is a neurotrophic factor for the adult rat RGC. GDNF, like BDNF, may be useful for the treatment of human RGC degenerative diseases.
成年大鼠视网膜神经节细胞（RGC）在视神经横断后会发生退变。研究表明，外源性应用神经营养因子，如脑源性神经营养因子（BDNF），可减轻轴突切断诱导的以及发育过程中的RGC死亡。在此，我们研究了胶质细胞系源性神经营养因子（GDNF），一种已知的对多巴胺能神经元和运动神经元起作用的神经营养因子，是否能为成年大鼠的RGC提供神经营养支持。我们确定RGC是否能从其靶组织逆行转运GDNF。将125I-GDNF注射到成年大鼠的上丘后，它能逆行转运至对侧眼，但不能转运至同侧眼。125I-GDNF的转运可被同时注射过量未标记的GDNF所阻断，表明这是受体介导的。我们测试了玻璃体内应用GDNF是否能预防轴突切断诱导的RGC退变。用荧光金（FG）对RGC进行预标记，并通过眶内视神经横断使其轴突切断。在第0天和第7天玻璃体内注射GDNF、BDNF（阳性对照）、细胞色素c（阴性对照）或GDNF/BDNF组合。在第14天，从视网膜全层标本中计数FG标记的RGC。我们发现，与BDNF相似，GDNF能以剂量依赖的方式显著减轻RGC的退变。此外，GDNF和BDNF联合治疗比单独使用任何一种因子都显示出更好的保护作用。我们的数据表明，GDNF是成年大鼠RGC的一种神经营养因子。与BDNF一样，GDNF可能对治疗人类RGC退行性疾病有用。
