Purchase this article with an account.
Kun-Che Chang, Linfeng Li, Biehuoy Shieh, Daniel Vincent LaBarbera, J Mark Petrash; Emodin Alleviates Aldose Reductase-Induced Cataract formation in Mouse Lens. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1154.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Many aldose reductase (AR, AKR1B1) inhibitors have been used for treatment of diabetic complications. However, many inhibitors suffer from poor selectivity and organ toxicity. The purpose of this study was to investigate whether Emodin, a natural compound from plants, provides a better and safer therapeutic effect against cataract formation.
IC50 and stability of Emodin were determined by AR activity assay. Aldo-keto reductase (AKR) 1B1, 1B10 and 1A1 were used for inhibitory selectivity of Emodin. In vitro and in vivo effects of Emodin were conducted using sorbitol accumulation assay, vacuolization measurement and lens culture (FHL 124). Computational modeling was carried out using the flexible docking protocol of Discovery Studio (V4.1, 3DS Biovia). The CHARMm force field was applied to the 1.08 Å AKR1B1 (PDB: 2FZD) crystal structure. Data were analyzed by Student’s t test with P value of <0.05 considered significant.
Emodin selectively inhibited AR (IC50 = 2.69 ± 0.90 μM) but did not inhibit AKR1B10 and AKR1A1, and was stable at 37 °C for 7 days. In vitro studies confirmed its inhibitory activity in the FHL 124 human lens cell lines using sorbitol accumulation assay. In animal model, we observed that AR transgenic mice spontaneously formed vacuoles in lenses in 16 days. Oral administration of Emodin successfully reduced vacuole formation by approximately 66% of total area in lenses of AR transgenic mice. According to inhibition kinetic studies, Emodin blocks AR in an uncompetitive manner with a corresponding inhibition constant Ki = 2.113 ± 0.095 μM. Computational modeling showing structural similarity between Emodin and Tolrestat indicated that 3-hydroxy of Emodin plays an essential role by interacting with the NADP+ cofactor and His110 through hydrogen bond in the anionic pocket of AR.
The findings in this study provide encouraging evidence for Emodin being a therapeutic agent for prevention of cataract formation. Understanding the structural modeling of Emodin that blocks AR active site provides a pharmaceutical direction for AR inhibitors development in the future.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
This PDF is available to Subscribers Only