Light induced retinal degeneration: Utility of OCT and corticosteroids to monitor and manage retinal damage

Abstract

Age-related macular degeneration (AMD) is a neurodegenerative disease of the central retina, resulting in irreversible vision loss. It is recognised as the leading cause of blindness in the Western world, primarily affecting those over the age of 50, with an expected prevalence of 288 million people by 2040. Inflammation is a cellular response that has been implicated in the pathogenesis of AMD. There are currently no treatments available for the more prevalent non-exudative form of AMD ('dry' AMD) making the development of therapeutic strategies of significant importance. Corticosteroids have been associated with mitigating inflammation, however the broader applications of their use in retinal degenerations is unknown.

The overarching aim of this thesis is to monitor and mitigate light induced, inflammation-mediated retinal degeneration in vitro and in vivo through the utility of optical coherence tomography (OCT) and corticosteroids. Through the use of OCT as a live imaging technique in animals, this thesis demonstrated retinal lesion development and expansion, progressive inflammation-mediated photoreceptor cell death and functional loss. This exhibited a close match in the damage detected by OCT and histology in rats, in addition to detecting photoreceptor cell death in mice. This study demonstrates the use of OCT as a diagnostic, analytical and innovative tool in animal models that has practical and clinical applications for retinal degenerative diseases such as AMD, by providing a real-time indicator that can capture the varying stages of progressive retinal disease.

In the investigation of corticosteroid-mediated mitigation of inflammation, both sub-types of corticosteroids, including glucocorticoids and mineralocorticoids were tested. This study confirms the anti-inflammatory properties of glucocorticoid, triamcinolone acetonide (TA), and mineralocorticoid, fludrocortisone acetate (FA), in Muller cells in vitro, known to be a key inflammatory mediator. The data suggests that FA may be a more potent anti-inflammatory agent, particularly in the presence of IL-1B-mediated inflammation. The data also show that the glucocorticoid receptor is the key receptor expressed in Muller cells, which mediates the effects of TA and FA.

Building on the in vitro data, I then used the photo-oxidative (PD) model of AMD, which mimics the features of AMD including retinal inflammation and photoreceptor cell loss, to investigate the efficacy of corticosteroids to dampen the inflammatory response and mitigate retinal damage, and to determine how the delivery vehicle might affect those outcomes. The findings validate the use of corticosteroids as anti-inflammatory agents in photoreceptor degeneration as a result of PD to the retina. This was exhibited and verified using histology, OCT and electroretinography (ERG) recordings. It was also demonstrated that FA has a higher anti-inflammatory potency than TA. It was further found that the anti-inflammatory properties of FA are dependent on the delivery vehicle. Collectively, this thesis identifies the therapeutic use of FA to mitigate inflammation in retinal degeneration, providing a useful avenue for further research in the treatment of AMD. Show more