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G Bhanuprakash Reddy, Ganugula Raghu, Puppala Methenna, Chandrasekhar Akileshwari, Palla Suryanarayana, Jonathan Mark Petrash; Inhibition of ALR2 and AGE formation by ellagic acid: Prevention or treatment of diabetic cataract and retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1056.
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© ARVO (1962-2015); The Authors (2016-present)
Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity and increased formation of advanced glycation endproducts (AGE) due to non-enzymatic glycation are implicated in the development of diabetic ocular complications such as retinopathy and cataract. We have identified a few dietary sources that have the potential to inhibit ALR2 and AGE formation. Ellagic acid (EA), a bioflavonoid is present in many of these dietary sources. In the present study, we described the inhibition of ALR2 and AGE formation by EA and investigated its potential to prevent diabetic cataract and retinopathy in rat model.
Antiglycating potential and mechanism of action of EA was investigated using in vitro protein glycation systems. Inhibition of ALR2 by EA was assessed using recombinant ALR2 assay and sorbitol estimation in RBC. Further the effect of EA to prevent diabetic cataract and retinopathy was investigated using streptozotocin-induced diabetic rat model.
EA inhibited ALR2 with an IC50 of 48 nM in a non-competitive manner. Further, EA suppressed sorbitol accumulation in human RBC, rat lens and rat retina under high glucose conditions. EA was effective in inhibiting the formation of AGE, predominantly inhibition of Nε-(carboxymethyl)lysine through scavenging of dicarbonyl compounds. EA also inhibited the formation of glycosylated Hb in human blood under high glucose conditions. The significance of EA against loss of eye lens transparency was demonstrated in lens organ culture system. Finally, physiological significance of EA was demonstrated in terms of delay of diabetic cataract and retinopathy in rats.
These findings together establish the antiglycating and ALR inhibitory potential of EA and its in vivo utility for controlling diabetic ocular pathologies. Thus, these observations suggest that EA holds a therapeutic promise to prevent or treat ocular complications of diabetes.
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