Whitmire Will, Al-Gayyar Mohammed Mh, Abdelsaid Mohammed, Yousufzai Bilal K, El-Remessy Azza B
Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 30912, USA.
Mol Vis. 2011 Jan 28;17:300-8.
Diabetic retinopathy (DR) is a leading cause of blindness in American adults. Over the years, DR has been perceived as a vascular disease characterized by vascular permeability, macular edema, and neovascularization that can lead to blindness. Relatively new research on neurodegeneration is expanding our views of the pathogenesis of DR. Evidence has begun to point to the fact that even before vascular complications begin to manifest, neuronal cell death and dysfunction have already begun. Based on the literature and our own studies, we address whether neuronal death is associated with loss of neurotrophic support due to less production of a given growth factor or due to impairment of its signaling events regardless of the level of the growth factor itself.
In this article we aimed to review the literature that looks at the neuronal side of DR and whether retinal neurons are adversely affected due to the lack of neurotrophic levels or activity. In particular, we examine the research looking at insulin, insulin-like growth factor, vascular endothelial growth factor, pigment epithelium-derived growth factor, brain-derived neurotrophic factor, and nerve growth factor.
Research shows that insulin has neurotrophic properties and that the loss of its pro-survival pathways may have a role in diabetic retinopathy. There is also evidence to suggest that exogenously administered insulin may have a role in the treatment of DR. Insulin-like growth factor has been shown to have a role in retinal neurogenesis and there is early evidence that it may also have neuroprotective effects. While there is evidence of neuroprotective effects of vascular endothelial growth factor, paradoxically, there is also an increased amount of apoptotic activity in retinal neurons despite an increased level of VEGF in the diabetic eye. Further research is necessary to elucidate the exact mechanisms involved. Pigment epithelium derived growth factor has retinal neuroprotective effects and shows evidence that it may be an avenue for future therapeutic use in DR. Brain-derived growth factor has been shown to have neuroprotective effects in the retina and there is also some evidence in diabetic rats that it may have some therapeutic potential in treating DR. Nerve growth factor has also been shown to have neuroprotective effects and research has begun to elucidate some of the pathways and mechanisms through which these effects occur.
Research has shown that there is some degree of neuronal death involved in DR. It is also evident that there are many growth factors involved in this process. Some of these growth factors have shown some potential as future therapeutic targets in DR. These findings should encourage further investigation into the mechanism of these growth factors, their potential for therapy, and the possibility of a new horizon in the clinical care of DR.
糖尿病视网膜病变（DR）是美国成年人失明的主要原因。多年来，DR一直被视为一种血管疾病，其特征为血管通透性增加、黄斑水肿和新生血管形成，这些可导致失明。关于神经退行性变的相对较新的研究正在拓展我们对DR发病机制的认识。有证据开始表明，甚至在血管并发症开始显现之前，神经元细胞死亡和功能障碍就已经开始了。基于文献和我们自己的研究，我们探讨神经元死亡是否与由于特定生长因子产生减少或其信号传导事件受损而导致的神经营养支持丧失有关，而不考虑生长因子本身的水平。
在本文中，我们旨在回顾关注DR神经元方面以及视网膜神经元是否因神经营养水平或活性缺乏而受到不利影响的文献。特别是，我们研究了关于胰岛素、胰岛素样生长因子、血管内皮生长因子、色素上皮衍生生长因子、脑源性神经营养因子和神经生长因子的研究。
研究表明胰岛素具有神经营养特性，其促生存途径的丧失可能在糖尿病视网膜病变中起作用。也有证据表明外源性给予胰岛素可能在DR治疗中起作用。胰岛素样生长因子已被证明在视网膜神经发生中起作用，并且有早期证据表明它也可能具有神经保护作用。虽然有证据表明血管内皮生长因子具有神经保护作用，但矛盾的是，尽管糖尿病眼中VEGF水平升高，但视网膜神经元中的凋亡活性也增加。需要进一步研究以阐明其中的确切机制。色素上皮衍生生长因子具有视网膜神经保护作用，并显示出它可能是未来用于DR治疗的途径的证据。脑源性生长因子已被证明在视网膜中具有神经保护作用，并且在糖尿病大鼠中也有一些证据表明它在治疗DR方面可能具有一定的治疗潜力。神经生长因子也已被证明具有神经保护作用，并且研究已开始阐明这些作用发生的一些途径和机制。
研究表明DR涉及一定程度的神经元死亡。同样明显的是，这个过程中有许多生长因子参与。其中一些生长因子已显示出作为DR未来治疗靶点的一些潜力。这些发现应鼓励进一步研究这些生长因子的作用机制、它们的治疗潜力以及DR临床护理新前景的可能性。
