Central Role of Oxidative Stress in Age-Related Macular Degeneration: Evidence from a Review of the Molecular Mechanisms and Animal Models

Abstract

Age-related macular degeneration (AMD) is a common cause of visual impairment in the elderly. There are very limited therapeutic options for AMD with the predominant therapies targeting vascular endothelial growth factor (VEGF) in the retina of patients afflicted with wet AMD. Hence, it is important to remind readers, especially those interested in AMD, about current studies that may help to develop novel therapies for other stages of AMD. This study, therefore, provides a comprehensive review of studies on human specimens as well as rodent models of the disease, to identify and analyze the molecular mechanisms behind AMD development and progression. The evaluation of this information highlights the central role that oxidative damage in the retina plays in contributing to major pathways, including inflammation and angiogenesis, found in the AMD phenotype. Following on the debate of oxidative stress as the earliest injury in the AMD pathogenesis, we demonstrated how the targeting of oxidative stress-associated pathways, such as autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, might be the futuristic direction to explore in the search of an effective treatment for AMD, as the dysregulation of these mechanisms is crucial to oxidative injury in the retina. In addition, animal models of AMD have been discussed in great detail, with their strengths and pitfalls included, to assist inform in the selection of suitable models for investigating any of the molecular mechanisms.

Eye-Light on Age-Related Macular Degeneration: Targeting Nrf2-Pathway as a Novel Therapeutic Strategy for Retinal Pigment Epithelium

“…RPE degeneration causes secondarily adverse effects on photoreceptors and choriocapillaris, finally leading to retinal alterations, visual loss and, in the worst cases, irreversible blindness (Ambati and Fowler, 2012). A consistent body of evidence elucidates the importance of dysregulated antioxidant mechanisms and oxidative stress in the development of AMD, and supports the possible association between Nrf2 deficiency and AMD (Datta et al, 2017;Abokyi et al, 2020). Nrf2-pathway is a master regulator of stress response in RPE; beside the well-documented role in the antioxidant cell defense, Nrf2 is also a key component of the transduction machinery to maintain proteostasis, that is altered in AMD (Pajares et al, 2016).…”

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

“…In particular, obese people present an increased number of autophagosomes due to the combination of increased inflammation with inhibition of the last steps of autophagy [147,148]. In elderly people, autophagy deficiency results in a reduced degradation of ROS-damaged proteins [151,152], although oxidative stress is one of the most potent activators of this mechanism.…”

Autophagy in Age-Related Macular Degeneration: A Regulatory Mechanism of Oxidative Stress

“…Additionally, photosensitive molecules (rhodopsin and lipofuscin) interact with light; they are related to oxidative stress induction and the death of photoreceptor cells. Taken together, high oxygen metabolism, continuous light exposure, high concentrations of polyunsaturated fatty acids, and the existence of photosensitizers make the retina prone to be affected by oxidative stress [53].…”

“…One of the mechanisms of retinal injury is the interaction between light and photosensitive molecules. The excessive activation of rhodopsin and light conduction can induce photoreceptor cell degeneration [53]. H 2 O 2 , a component of ROS, is also widely used to stimulate oxidative stress in both in vivo animal models and in vitro RPE cell culture models [59].…”