Natural compounds as lead therapeutic agents against diabetic eye disease

Diabetes is a leading cause of new cases of blindness throughout the world. Given the rapid increase in diabetes incidence in recent years, diabetic eye disease will likely become an even bigger problem in the future. There are currently no medical therapies for prevention of early stage ophthalmic complications of diabetes, and treatment for late stage disease is complicated and prohibitively expensive for deployment on a large scale. We have centered our efforts on identifying therapeutic compounds identified as natural products, with a particular focus on plant materials identified over time to be associated with efficacy against diabetes and its complications. The Indian gooseberry (Emblica officinalis), commonly known as Amla, is used in the practice of Indian traditional medicine (Ayurveda) to minimize the effects of diabetes and its complications. We previously showed that treatment of experimentally diabetic rats with crude extracts from Amla fruit delayed the onset and progression of cataracts and prevented the accumulation of sorbitol and diabetes‐induced markers of lipid peroxidation and protein oxidation products in the eye. Because these results were consistent with the effects of aldose reductase (AR) inhibition, we embarked on a bioassay‐guided scheme to search for putative AR inhibitors (ARI), using human AR (AKR1B1) activity as an assay read out. Fractionation of materials in an Amla extract resolved several compounds with ARI activity. Structure elucidation by NMR identified the major inhibitor as 1‐O‐galloyl‐beta‐D‐glucose, also known as beta‐glucogallin (bGG). We and others have shown that AR inhibition by sorbinil and a variety of other validated ARIs suppresses inflammatory markers associated with exposure to lipopolysaccharide (LPS) endotoxins. Our studies show that treatment of LPS‐exposed mice with bGG dose‐dependently suppresses infiltration of inflammatory cells in the anterior and posterior chambers and prevents morphological disruption of retinal layers. Using macrophage cell cultures, we demonstrated that bGG down‐regulates endotoxin‐induced expression of a variety of pro‐inflammatory cytokines including TNFa and IL1b. Similar studies are being carried out with a novel drug lead recently identified in a family of flowering plants commonly cultivated in India and Malaysia (Piperaceae). Overall, our studies suggest that natural products may be a rich source of lead compounds useful for development as therapeutic agents against diabetic complications.