Neuroprotection as a therapeutic target in diabetic retinopathy: a basic approach

Abstract

PurposeTo test the hypothesis that protecting retinal neurons from apoptosis elicited by diabetic stress may prevent the increase of vascular endothelial growth factor (VEGF) in the retina.MethodsEx vivo mouse retinal explants were exposed to stressors similar to those characterizing diabetic retinopathy (DR), i.e. high glucose (HG), oxidative stress (OS) or advanced glycation end‐products (AGE). Retinal cell death was antagonized with octreotide (OCT), a somatostatin analog, and pituitary adenylate cyclase activating peptide (PACAP), two well‐documented neuroprotectants. Data were obtained with real time RT‐PCR, Western blot, ELISA and immunohistochemistry.ResultsControl explants remained viable up to 10 days. Increased apoptosis was observed after HG, OS or AGE, and it was paralleled by increases in VEGF expression and release. Both OCT and PACAP reduced retinal apoptosis. At the same time, they also reduced VEGF expression and release. To get indications about the biological significance of VEGF release by stressed retinal cells, a VEGF trap (VT) was administered to HG, OS or AGE treated retinal explants. The effect of the VT was to further increase cell death induced by treatments.ConclusionsProtecting retinal neurons from diabetic stress also reduces VEGF expression and release, while inhibiting VEGF leads to exacerbation of apoptosis. This suggests that the retina in early DR releases VEGF as a pro‐survival factor. Neuroprotective agents may decrease the need of VEGF production by the retina, therefore limiting the risk, in the long term, of pathologic angiogenesis.