Old and New Drug Targets in Diabetic Retinopathy: From Biochemical Changes to Inflammation and Neurodegeneration

Abstract

Diabetic Retinopathy (DR) is a major complication of diabetes and is a leading cause of blindness in western countries. DR has been considered a microvascular disease, and the blood-retinal barrier breakdown is a hallmark of this disease. The available treatments are scarce and not very effective. Despite the attempts to control blood glucose levels and blood pressure, many diabetic patients are affected by DR, which progresses to more severe forms of disease, where laser photocoagulation therapy is needed. DR has a huge psychological impact in patients and tremendous economic and social costs. Taking this into account, the scientific community is committed to find a treatment to DR. Understanding the cellular and molecular mechanisms underlying the pathogenesis of DR will facilitate the development of strategies to prevent, or at least to delay the progression of the disease. The involvement of the polyol pathway, advanced glycation end products, protein kinase C and oxidative stress in the pathogenesis of DR is well-documented, and several clinical trials have been conducted to test the efficacy of various drugs. More recent findings also demonstrate that DR has characteristics of chronic inflammatory disease and neurodegenerative disease, which increases the opportunity of intervention at the pharmacological level. This review presents past and recent evidences demonstrating the involvement of different molecules and processes in DR, and how different approaches and pharmacological tools have been used to prevent retinal cell dysfunction.

Suppressors of Cytokine-Signaling Proteins Induce Insulin Resistance in the Retina and Promote Survival of Retinal Cells

“…4B and C), consistent with requirement of STAT3 for transcription of VEGF and HIF-1␣ mRNA (35,36,44). While VEGF may provide prosurvival functions in retina, accumulation of VEGF in the eye is implicated in the development of retinopathies, and anti-VEGF antibody is effective in treatment of diabetic retinal neovascularization (45). These diametrically polar effects of VEGF in the retina suggest that STAT3-induced VEGF expression is exquisitely regulated in the retina, as activated STAT3 is preferentially localized to neovascular retinal vessels in a mouse model of ischemia-induced retinal neovascularization (46).…”

NPY in rat retina is present in neurons, in endothelial cells and also in microglial and Müller cells

“…Some studies strongly suggest that retinal macroglia and microglia may be associated with retinal dysfunctions such as vitreoretinopathy, diabetic retinopathy, retinitis pigmentosa and age-related macular degeneration (Gupta et al, 2003;McGillem and Dacheux, 1998;RunggerBrandle et al, 2000;Soler et al, 2002). Therefore, the presence of NPY in retinal microglia may suggest a putative role of this peptide on inflammatory states observed in those retinal dysfunctions and should be further investigated (Leal et al, 2005;Meleth et al, 2005;Zhou et al, 2005).…”

Neuroretinal Dysfunction With Intact Blood-Retinal Barrier and Absent Vasculopathy in Type 1 Diabetes

“…However, if early neural damage occurs, it can be studied by searching for evidence of neuroretinal changes in the absence of retinal microvasculopathy. This is possible in the pre-DR stage (14)(15)(16)(17). Some functional studies have suggested visual impairment in diabetic patients without apparent DR, but these studies did not exclude changes in integrity of the barrier function using a quantitative method (2,(18)(19)(20)(21)(22)(23)(24)(25).…”