Attenuation of diabetic retinopathy in rats by ellagic acid through inhibition of AGE formation.

Diabetic retinopathy (DR) is a major concern for blindness all over the world. Diabetic retinopathy is associated with thickening of basement membrane, retinal thinning, retinal detachment, and pericyte death. Advanced glycation end products (AGEs) mediate the progression of DR by stimulating the expression of RAGE and VEGF which subsequently damages the blood-retinal barrier. Employing a set of in vitro protein glycation systems, earlier we demonstrated antiglycating potential of ellagic acid (EA). In this study, we evaluated the efficacy of EA to prevent in vivo accumulation of AGE and to ameliorate retinal changes in diabetic rats. Streptozotocin-induced diabetic rats were fed either with 0.2 or 2% EA in the diet for 12 weeks. Effect of EA on retinal function was assessed with electroretinogram (ERG). At the end of the experiment, rats were scarified and retina was collected. Histology was carried out with H&E staining and immunohistochemistry. Formation of AGE product (CML) and activation of RAGE was analyzed by immunoblotting and immunohistochemistry. Expression of GFAP, VEGF, Bax and HIF-1α was assessed by qRT-PCR and immunoblotting. Dietary supplementation of EA to diabetic rats resulted in: (1) inhibition of accumulation of CML and activation of RAGE in retina, (2) attenuation of expression of GFAP, VEGF, and HIF-1α in retina, (3) attenuation of cell death by reducing proapoptic mediator Bax and (4) amelioration of retinal thickness and function. In conclusion, EA attenuated the retinal abnormalities including angiogenesis, hypoxia and cell death by inhibiting AGE-RAGE mediated cellular events.