Oral Administration Of Alpha-Cyclodextrin Corrects Diabetes Induced Retinopathy And Bone Marrow Pathology By Modulation Of The Gut-Retina Axis.

Authors

• Yvonne Adu-Agyeiwaah, University of Alabama at Birmingham

Advisor(s)

Maria Grant

Committee Member(s)

Jillian Ziemanski
Julia Busik
Lawrence Sincich
Timothy Kraft

School

School of Optometry

Document Type

Dissertation

Department (new version)

Vision Science

Date of Award

9-9-2024

Abstract

Diabetic retinopathy represents a common complication of diabetes, exerting a significant financial burden globally across nations, particularly impacting the working-age population and thereby affecting productivity. Extensive investigations have unveiled its multifaceted etiology, implicating a convergence of diverse causative factors. Notably, seminal studies such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study have underscored the pivotal role of cholesterol dysregulation and dyslipidemia in the pathogenesis of diabetic retinopathy. This dysregulation stems from an imbalance characterized by heightened cholesterol production coupled with deficient cholesterol efflux or removal mechanisms. Liver X receptors (LXRs), ligand-activated nuclear receptors function in transcriptional regulation of lipid metabolism and inflammation. This receptor subfamily comprises two members, LXRα and LXRβ (NR1H3 and NR1H2, respectively), with endogenous ligands including oxysterols. Activation of the Liver X Receptor (LXR) pathway causes the upregulation of genes crucial for reverse cholesterol transport, notably including ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1), facilitating the removal of excess cholesterol from tissues. Our investigations have elucidated that Sirtuin 1 (SIRT1), an NAD-dependent deacetylase, serves as a positive modulator of the LXR pathway. Treatment with SIRT1 in bovine retinal endothelial cells yielded decreased cholesterol levels in diabetic conditions. Systemic administration of SIRT1 to diabetic mice led to attenuated inflammation and diminished cellular apoptosis. Remarkably, targeted intravitreal administration of SIRT1 to the retina of diabetic mice resulted in reduced retinal inflammation, cellular apoptosis, hypoxia, along with enhanced retinal electrical response amplitudes and visual acuity. These findings collectively highlight the therapeutic potential of increasing cholesterol efflux pathways via mechanisms such as SIRT1 activation in ameliorating diabetic retinopathy. Additionally, investigations have highlighted the tendency for cholesterol accumulation to precipitate crystallization, particularly under conditions characterized by alterations in temperature, pH, and elevated levels of saturation. Using our established mouse model of diabetes, specifically the db/db mouse, we detected the presence of cholesterol crystals within the diabetic retina, with their onset observed as early as 2 months following the onset of diabetes (corresponding to 4 months of age). We hypothesized that these cholesterol crystals within the retina serve as sterile particulate signals, which can act as damage-associated molecular pattern molecules (DAMPs), thereby instigating an inflammatory cascade within the retina in diabetes. Consequently, this cascade may contribute substantively to the pathogenesis underlying diabetic retinopathy. Alpha-cyclodextrin, a cyclic oligosaccharide recognized for its safety by the Food and Drug Administration, demonstrates the capacity to efficiently eliminate cholesterol crystals both in vitro and in vivo. In our investigation involving diabetic mice, we implemented this application and noted a substantial reduction in retinal cholesterol crystals. Concurrently, we observed diminished retinal inflammation and decreased recruitment of immune cells. Further examination revealed a notable reduction in retinal microvascular pathology, as evidenced by the enumeration of acellular capillaries. Moreover, we observed a correction of gut dysbiosis, a common occurrence in diabetes, alongside improvements in gut barrier integrity and increases in bacteria that generate beneficial secondary bile acids. Additionally, deviations from normal hematopoiesis were rectified towards levels akin to those observed in control mice. Beyond its direct action in dissolving and eliminating cholesterol crystals, other studies suggest that alpha-cyclodextrin activates the LXR pathway, facilitating efflux of excessive cholesterol. This dual mechanism of action underscores its potential in restoring both cholesterol and systemic homeostasis. Alpha-cyclodextrin presents a promising therapeutic strategy to potentially transform the treatment landscape for diabetic retinopathy. We demonstrate its efficacy in our animal studies and notable benefits suggestive of potential avenues for intervention.

ProQuest ID

https://proquest.com/docview/3101846791