title: Alteration of growth factors and neuronal death in diabetic retinopathy: what we have learned so far.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 30912, USA.
authors.forename: Will
authors.initials: W
authors.lastname: Whitmire
authors.forename: Mohammed Mh
authors.initials: MM
authors.lastname: Al-Gayyar
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abdelsaid
authors.forename: Bilal K
authors.initials: BK
authors.lastname: Yousufzai
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015843:Serpins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005136:Eye Proteins; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D036341:Intercellular Signaling Peptides and Proteins; D020932:Nerve Growth Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor