Koeberle Paulo D, Ball Alexander K
McMaster University, Anatomy, HSC 1R1, 1200 Main Strreet West, L8N 3Z5, Hamilton, ON, Canada.
Neuroscience. 2002;110(3):555-67. doi: 10.1016/s0306-4522(01)00557-7.
In the present study we localized glial cell line-derived neurotrophic factor (GDNF), and the high affinity receptor for GDNF (GFRalpha-1) in the rat retina. We also examined the effects of neurturin on the survival of axotomized retinal ganglion cells (RGCs) and compared neurturin-mediated RGC rescue to GDNF and brain-derived neurotrophic factor (BDNF) neuroprotection. We administered combined injections of neurturin with BDNF or GDNF in order to determine if these factors rescue RGCs by different mechanisms. GDNF immunoreactivity was localized to RGCs, photoreceptors, and retinal pigment epithelial cells. GFRalpha-1 immunoreactivity was localized to RGCs, Müller cells, and photoreceptors. RGC densities in control retinas decreased from the original value of 2481+/-121 (RGCs/mm(2)+/-S.D.) to 347+/-100 at 14 days post-axotomy. Neurturin treatment significantly increased RGC survival after axotomy (745+/-94) similar to GDNF (868+/-110). BDNF treatment resulted in higher RGC survival (1109+/-156) than either neurturin or GDNF. Combined administration of neurturin with BDNF had additive effects on the survival of axotomized RGCs (1962+/-282), similar to combined administration of GDNF and BDNF (1825+/-269). Combined administration of neurturin and GDNF (1265+/-178) had an enhanced effect on RGC survival. These results suggest that neurturin, GDNF, and BDNF act independently to rescue injured RGCs. Our results also suggest that RGCs and retinal Müller cells may be responsive to GDNF because they both express GFRalpha-1. The present findings have implications for the rescue of injured retinal ganglion cells, as well as other CNS neurons that are responsive to neurturin, GDNF, and BDNF, including midbrain dopaminergic neurons and motor neurons.
在本研究中，我们在大鼠视网膜中定位了胶质细胞系源性神经营养因子（GDNF）及其高亲和力受体GDNF（GFRalpha-1）。我们还研究了神经营养素对切断轴突的视网膜神经节细胞（RGCs）存活的影响，并将神经营养素介导的RGCs挽救作用与GDNF和脑源性神经营养因子（BDNF）的神经保护作用进行了比较。我们联合注射神经营养素与BDNF或GDNF，以确定这些因子是否通过不同机制挽救RGCs。GDNF免疫反应性定位于RGCs、光感受器和视网膜色素上皮细胞。GFRalpha-1免疫反应性定位于RGCs、米勒细胞和光感受器。轴突切断术后14天，对照视网膜中的RGC密度从原始值2481±121（RGCs/mm²±标准差）降至347±100。神经营养素治疗显著增加了轴突切断术后RGCs的存活率（745±94），与GDNF（868±110）相似。BDNF治疗导致的RGCs存活率（1109±156）高于神经营养素或GDNF。神经营养素与BDNF联合给药对切断轴突的RGCs存活有相加作用（1962±282），与GDNF和BDNF联合给药（1825±269）相似。神经营养素和GDNF联合给药（1265±178）对RGCs存活有增强作用。这些结果表明，神经营养素、GDNF和BDNF独立发挥作用以挽救受损的RGCs。我们的结果还表明，RGCs和视网膜米勒细胞可能对GDNF有反应，因为它们都表达GFRalpha-1。本研究结果对挽救受损的视网膜神经节细胞以及其他对神经营养素、GDNF和BDNF有反应的中枢神经系统神经元具有重要意义，包括中脑多巴胺能神经元和运动神经元。
