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

Abstract

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.

Capability of polygonum cuspidatum extract in inhibiting AGEs and preventing diabetes

“…The free radical scavenging activities played as the antioxidant role in the chain‐breaking performance on glycoxidation as exemplified in the study of Ardestani and Yazdanparast () and Suantawee et al (). For example, ellagic acid has been reported to inhibit AGE formation in diabetic mice and decrease the level of CML (Raghu, Akileshwari, Reddy, & Reddy, ). Coumarin has also been demonstrated to have antiglycation effect because the hydroxyl group of aromatic ring in coumarin molecule hinders the incorporation of albumin with glucose, thereby interferes with glycation and AGE formation (Aminjafari et al, ).…”

“…For example, ellagic acid has been reported to inhibit AGE formation in diabetic mice and decrease the level of CML (Raghu, Akileshwari, Reddy, & Reddy, 2017). Coumarin has also been demonstrated to have antiglycation effect because the hydroxyl group of aromatic ring in coumarin molecule hinders the incorporation of albumin with glucose, thereby interferes with glycation and AGE formation (Aminjafari et al, 2016).…”

Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

“…Over the last decades, available knowledge of the mechanisms involved in AGEs formation has led to attempts to inhibit the formation of AGEs. Different sources including several endogenous glycolytic and oxidative pathways, as well as exogenous diet-derived sources were reported [73,74]. A number of compounds such as benfotiamine, aminoguanidine, pyridoxamine, carnosine and phenyl thiazolium bromide have been investigated on the property of anti-AGEs activity [73].…”

“…Different sources including several endogenous glycolytic and oxidative pathways, as well as exogenous diet-derived sources were reported [73,74]. A number of compounds such as benfotiamine, aminoguanidine, pyridoxamine, carnosine and phenyl thiazolium bromide have been investigated on the property of anti-AGEs activity [73]. As a well-known AGEs inhibitor, pyridoxamine ameliorated DR in experimental diabetic rats and as yet it is the only compounds that passed the phase III clinical trials [75].…”

Hypoglycemic, Antiglycation and Cytoprotective Properties of A Phenol Rich Extract from Waste Peel of <i>Punica Granatum</i> L. Var. Dente Di Cavallo DC2

“…Particularly, a pomegranate flower extract rich in gallic acid showed to increase the PPAR-gamma mRNA expression along with enhancing the sensitivity to insulin receptor, thus suggesting that this mechanism could be involved in the control of AGE formation [60]. Similarly, ellagic acid exhibited interesting antiglycation properties both in vitro and in vivo, by reducing the expression of RAGE along with that of specific regulatory factors for angiogenesis and hypoxia, thus suggesting it can represent a potent antiglycating agent to be further developed [61]. This evidence, in agreement with the previous described antioxidant, glycolytic enzyme inhibitory and chelating properties, strengthen our hypothesis about a possible role of PGE phytocomplex in the control of hyperglycemia-related ailments and suggest the need of further in vivo evaluation of its potential usefulness in diabetic animal models.…”