MULTIPLE GROWTH-FACTORS, CYTOKINES, AND NEUROTROPHINS RESCUE PHOTORECEPTORS FROM THE DAMAGING EFFECTS OF CONSTANT LIGHT
MULTIPLE GROWTH-FACTORS, CYTOKINES, AND NEUROTROPHINS RESCUE PHOTORECEPTORS FROM THE DAMAGING EFFECTS OF CONSTANT LIGHT
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DOI：
10.1073/pnas.89.23.11249
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发表时间：
1992-12-01
影响因子：
11.1
通讯作者：
STEINBERG, RH
中科院分区：
文献类型：
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作者：
LAVAIL, MM;UNOKI, K;STEINBERG, RH
最近的证据表明，神经营养剂在不同的神经系统中的生存促进活性，提高了中枢神经系统遗传性和退行性疾病的药物治疗的可能性。我们先前已经证明，在视网膜中，碱性成纤维细胞生长因子延迟患有遗传性视网膜营养不良的皇家外科医学院大鼠的感光细胞变性，并且生长因子减少或防止大鼠中由恒定光照产生的感光细胞快速变性。这种光损伤模型现在提供了一种有效的方法来定量评估许多生长因子和其他分子在体内的生存促进活性。我们在这里报告，光感受器可以显着保护光的破坏性影响，玻璃体内注射8种不同的生长因子，细胞因子和神经营养因子，通常通过几个不同的受体家族。 除碱性成纤维细胞生长因子外，提供高度光感受器拯救的因子包括脑源性神经营养因子、睫状神经营养因子、白细胞介素1 β和酸性成纤维细胞生长因子;活性较低的因子包括神经营养因子3、胰岛素样生长因子II和肿瘤坏死因子α;显示很少或没有保护作用的是神经生长因子、表皮生长因子、血小板衍生生长因子、胰岛素、胰岛素样生长因子I、肝素和层粘连蛋白。尽管我们使用了每种药剂的至少一种相对较高的浓度（可用的最高浓度），但仍有可能其他浓度或因子组合可能更具保护性。注射肝素沿着酸性成纤维细胞生长因子或碱性成纤维细胞生长因子进一步增强了感光细胞存活的程度，并且还抑制了由任一因子（尤其是碱性成纤维细胞生长因子）产生的巨噬细胞的增加的发生率。这些结果现在为确定每种药物在视网膜中的正常功能、拯救机制和人类眼病中的治疗潜力提供了动力。
Recent demonstrations of survival-promoting activity by neurotrophic agents in diverse neuronal systems have raised the possibility of pharmacological therapy for inherited and degenerative disorders of the central nervous system. We have shown previously that, in the retina, basic fibroblast growth factor delays photoreceptor degeneration in Royal College of Surgeons rats with inherited retinal dystrophy and that the growth factor reduces or prevents the rapid photoreceptor degeneration produced by constant light in the rat. This light-damage model now provides an efficient way to assess quantitatively the survival-promoting activity in vivo of a number of growth factors and other molecules. We report here that photoreceptors can be significantly protected from the damaging effects of light by intravitreal injection of eight different growth factors, cytokines, and neurotrophins that typically act through several distinct receptor families. In addition to basic fibroblast growth factor, those factors providing a high degree of photoreceptor rescue include brain-derived neurotrophic factor, ciliary neurotrophic factor, interleukin 1beta, and acidic fibroblast growth factor; those with less activity include neurotrophin 3, insulin-like growth factor II, and tumor necrosis factor alpha; those showing little or no protective effect are nerve growth factor, epidermal growth factor, platelet-derived growth factor, insulin, insulin-like growth factor I, heparin, and laminin. Although we used at least one relatively high concentration of each agent (the highest available), it is still possible that other concentrations or factor combinations might be more protective. Injecting heparin along with acidic fibroblast growth factor or basic fibroblast growth factor further enhanced the degree of photoreceptor survival and also suppressed the increased incidence of macrophages produced by either factor, especially basic fibroblast growth factor. These results now provide the impetus for determining the normal function in the retina, mechanism(s) of rescue, and therapeutic potential in human eye diseases for each agent.