Oral administration of alpha-cyclodextrin reverses diabetic retinopathy in db/db mice

Abstract

Purpose : We hypothesized that high cholesterol levels leading to the formation of cholesterol crystals in the diabetic retina contribute to DR pathology and vision loss. Alpha-cyclodextrin, a cyclic oligosaccharide lowers cholesterol levels and improves atherosclerotic lesions. In this study, we investigated the effect of alpha-cyclodextrin on cholesterol crystals-induced retinal damage in DR.

Methods : Four-month-old db/db mice were given either oral alpha-cyclodextrin incorporated in their diet (21g/kg body weight) or a control diet. Mice were euthanized after 4 months of treatment. Measurement of Electroretinograms (ERG) and Optomotor kinetic (OKN) responses were undertaken to determine the retinal neural function and visual response respectively before euthanization. Eyes were collected for Scanning Electron Microscopy (SEM) and Immunohistochemistry for macroglia reactivity using Glial fibrillary acidic protein (GFAP).

Results : We observed the removal of cholesterol crystals from the retinas of diabetic mice with oral alpha-cyclodextrin treatment. GFAP reactivity was significantly reduced in the retinal macroglia cells of diabetic mice with oral alpha-cyclodextrin treatment (677.70 ± 204.51 vs 888.65 ± 218.29, p<0.05) compared to that of standard chow-fed diabetic mice. The a-wave in the ERG photopic response in alpha-cyclodextrin treated db/db mice was significantly improved compared to db/db mice (133.81 ± 20.58 vs 73.51 ± 36.6, p<0.05), and OKN responses were also improved in alpha-cyclodextrin treated db/db mice (0.41 ± 0.02 vs 0.37 ± 0.03, p<0.05) compared to the control diet treated db/db mice.

Conclusions : We demonstrate that cholesterol crystal-induced retinal pathology occurs in diabetes and contributes to DR which is improved by the use of oral alpha-cyclodextrin. We show that in addition to the reduction in retinal inflammation, treatment can preserve retinal neural cells, and subsequently retinal visual function and response can be restored using this therapy.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.