Posted by Dyslipidemia is common in individuals with T2D and clinical studies show cholesterol and lipid management reduce diabetic retinopathy (DR) progression. It was previously shown that excessive cholesterol accumulation can lead to cholesterol crystals formation promoting DR pathology. Alpha-cyclodextrin, a cyclic oligosaccharide eliminates cholesterol crystals in atherosclerotic lesions. In this study, the effect of oral alpha-cyclodextrin administration was investigated on retinal cholesterol crystal formation in T2D mice and changes in DR severity.
An alpha-cyclodextrin incorporated diet (21g/kg body weight) or control diet was fed to db/db mice with 2 months duration of diabetes. Mice were euthanized after 4 months of drug treatment. Electroretinograms (ERG) and Optomotor kinetic (OKN) response measurements were done to assess retinal function and visual response respectively. Retina tissue was used for immunohistochemistry for microglia and macroglia reactivity using Ionized calcium-binding adaptor molecule 1 (Iba1) and Glial fibrillary acidic protein (GFAP), respectively. Retina immune cells were also characterized by flow cytometry.
Cholesterol crystals were eliminated from the retinas of diabetic mice after oral alpha-cyclodextrin treatment. Treated diabetic mice had reduced GFAP reactivity in the retina (677.70 ± 204.51 vs 888.7 ± 218.29, p<0.001) compared to normal chow fed diabetic mice. Iba1+ cells were increased in db/db mice retina and reduced in the oral alpha-cyclodextrin treated mice (8.3±2.3 vs 4.8±2.4, p<0.001). Classical monocytes were increased in the retina of T2D mice and reduced by alpha-cyclodextrin treatment (86.30±6.2 vs 28.8±15.70, p<0.003). Non-classical monocytes were reduced in diabetic retina and increased by alpha-cyclodextrin treatment (12.7±5.59 vs 70.85±4.15, p<0.001). The ERG photopic b-wave response in alpha-cyclodextrin treated db/db mice was significantly improved compared to db/db mice (133.81±7.78 vs 73.51±15.81, p<0.001). OKN responses were similarly improved in alpha-cyclodextrin-treated db/db mice (0.41 ± 0.02 vs 0.37 ± 0.03, p<0.001) compared to the control diet-fed db/db mice.
Conclusions : These findings demonstrate that T2D is associated with cholesterol crystal-induced retinal pathology that is improved using oral alpha-cyclodextrin: an improvement in inflammation, neural function and visual response was observed.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.
Yvonne Adu-Agyeiwaah; Bright Asare-Bediako; Jason Floyd; Mariana D DuPont; Cristiano Vieira; Ram Prasad; Sergio Li Calzi; Irina A Pikuleva; Julia V. Busik; Maria B Grant (2023) Oral alpha-cyclodextrin reverses cholesterol-crystal-induced retinal pathology in a rodent model of type 2 diabetes (T2D). Investigative Ophthalmology & Visual Science 64, 1834. https://iovs.arvojournals.org/article.aspx?articleid=2786825