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M. Puppala, S. Palla, P. Y. Reddy, S. K. Gunda, J. M. Petrash, G. B. Reddy; Mechanism, Specificity, and Significance of Aldose Reductase Inhibition by Curcumin. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3819. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2 or AKR1B1) activity has been implicated in the development of diabetic complications such as cataract and retinopathy. Hence, we investigated the effect of curcumin, a dietary antioxidant present in the commonly used spice Curcuma longa on aldose reductase activity and on hyperglycemia-induced changes in lens and retina.
Inhibition of members of aldo-keto reductase (AKR) superfamily, human recombinant aldose reductase (AKR1B1) and human small intestine reductase (AKR1B10) and bovine kidney aldehyde reductase (ALR1) by curcumin was determined by spectrophotometric assays. Kinetic constants, Km and Vmax of recombinant AKR1B1 were determined with varying concentrations of glyceraldehyde as substrate in presence of curcumin by Lineweaver-Burk double reciprocal plots. Binding constant (Kd) and sorbinil displacement were determined by fluorescence titration with curcumin and sorbinil respectively. Inhibition of AKR1B1 and AKR1B10 and specificity for AKR members for keto and enol forms of three major curcuminoids were determined by molecular docking studies. The potential of curcumin to suppress the formation of sorbitol in red blood cells under high glucose conditions and to prevent hyperglycemia-mediated changes in lens and retina of diabetic rat was investigated. VEGF expression was measured by western blotting and real time PCR.
Curcumin inhibited aldose reductase (AKR1B1) with an IC50 of 10 µM in a non-competitive manner, but was a poor inhibitor of AKR1B10 and ALR1. Molecular docking data were consistent with the pattern of inhibition of AKR1B1 by curcumin and its specificity and indicate that both keto and enol forms have similar effects. Moreover, curcumin was able to suppress sorbitol accumulation in red blood cells under high glucose conditions. Further, these results could be translated to in vivo conditions as curcumin was effective in delaying experimentally-induced diabetic cataract in rats and inhibition of vascular endothelial growth factor (VEGF) in diabetic rat retina.
These results suggest that curcumin might be useful for the treatment and/ or prevention of diabetic ocular complications.
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