LaVail M M, Yasumura D, Matthes M T, Lau-Villacorta C, Unoki K, Sung C H, Steinberg R H
Department of Anatomy, University of California, San Francisco 94143-0730, USA.
Invest Ophthalmol Vis Sci. 1998 Mar;39(3):592-602.
To examine the protective effect of a number of survival factors on degenerating photoreceptors in mutant mice with naturally occurring inherited retinal degenerations, including retinal degeneration (rd/rd), retinal degeneration slow (rds/rds), nervous (nr/nr), and Purkinje cell degeneration (pcd/pcd), in three different forms of mutant rhodopsin transgenic mice and in light damage in albino mice.
Various survival factors were injected intravitreally into one eye of mice at or soon after the beginning of photoreceptor degeneration, with the opposite eye serving as the control, and the eyes were examined histologically at later ages. The survival factors included brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4, ciliary neurotrophic factor (CNTF), Axokine (a mutein of CNTF), leukemia inhibitory factor, basic fibroblast growth factor, and nerve growth factor and insulin-like growth factor II, either alone or in various combinations.
Photoreceptor degeneration was slowed in rd/rd and nr/nr mutant mice and in Q344ter mutant rhodopsin mice by certain forms of CNTF; the degeneration in Q344ter mice was slowed by Axokine and by leukemia inhibitory factor; and the degeneration in a few nr/nr mice was slowed by BDNF. The other agents were ineffective in these mice, and none of the agents were effective in the other mutants and other mutant rhodopsin transgenic mice. However, light damage experiments that compared agent effectiveness in albino mice versus rats suggested a significant delivery problem with the very small mouse eye, thereby making the interpretation of negative findings equivocal in mutant mice. Basic fibroblast growth factor failed to protect the mouse retina from the damaging effects of constant light, whereas it showed a strong protective effect in the rat, indicating an important species difference.
The slowing of degeneration in the rd/rd and Q344ter mutant mice demonstrated that intraocularly injected survival factors can protect photoreceptors from degenerating in animal models with the same or similar genetic defects as those in human inherited retinal degenerations.
研究多种生存因子对患有自然发生的遗传性视网膜变性的突变小鼠（包括视网膜变性（rd/rd）、视网膜变性缓慢（rds/rds）、神经（nr/nr）和浦肯野细胞变性（pcd/pcd））、三种不同形式的突变视紫红质转基因小鼠以及白化病小鼠光损伤中退化的光感受器的保护作用。
在光感受器退化开始时或之后不久，将各种生存因子玻璃体内注射到小鼠的一只眼睛中，对侧眼睛作为对照，在之后的年龄段对眼睛进行组织学检查。生存因子包括脑源性神经营养因子（BDNF）、神经营养因子-3、神经营养因子-4、睫状神经营养因子（CNTF）、Axokine（CNTF的一种突变蛋白）、白血病抑制因子、碱性成纤维细胞生长因子、神经生长因子以及胰岛素样生长因子II，单独使用或各种组合使用。
某些形式的CNTF减缓了rd/rd和nr/nr突变小鼠以及Q344ter突变视紫红质小鼠中的光感受器退化；Axokine和白血病抑制因子减缓了Q344ter小鼠中的退化；少数nr/nr小鼠中的退化被BDNF减缓。其他因子在这些小鼠中无效，并且没有一种因子在其他突变体和其他突变视紫红质转基因小鼠中有效。然而，比较白化病小鼠与大鼠中因子有效性的光损伤实验表明，小鼠眼睛非常小存在显著的递送问题，从而使得在突变小鼠中对阴性结果的解释模棱两可。碱性成纤维细胞生长因子未能保护小鼠视网膜免受持续光照的损伤作用，而它在大鼠中显示出强大的保护作用，表明存在重要的物种差异。
rd/rd和Q344ter突变小鼠中退化的减缓表明，玻璃体内注射的生存因子可以保护光感受器在具有与人类遗传性视网膜变性相同或相似遗传缺陷的动物模型中不发生退化。
