Suppression of Light-Induced Oxidative Stress in the Retina by Mitochondria-Targeted Antioxidant

Abstract

Light-induced oxidation of lipids and proteins provokes retinal injuries and results in progression of degenerative retinal diseases, such as, for instance, iatrogenic photic maculopathies. Having accumulated over years retinal injuries contribute to development of age-related macular degeneration (AMD). Antioxidant treatment is regarded as a promising approach to protecting the retina from light damage and AMD. Here, we examine oxidative processes induced in rabbit retina by excessive light illumination with or without premedication using mitochondria-targeted antioxidant SkQ1 (10-(6’-plastoquinonyl)decyltriphenyl-phosphonium). The retinal extracts obtained from animals euthanized within 1–7 days post exposure were analyzed for H2O2, malondialdehyde (MDA), total antioxidant activity (AOA), and activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) using colorimetric and luminescence assays. Oxidation of visual arrestin was monitored by immunoblotting. The light exposure induced lipid peroxidation and H2O2 accumulation in the retinal cells. Unexpectedly, it prominently upregulated AOA in retinal extracts although SOD and GPx activities were compromised. These alterations were accompanied by accumulation of disulfide dimers of arrestin revealing oxidative stress in the photoreceptors. Premedication of the eyes with SkQ1 accelerated normalization of H2O2 levels and redox-status of lipids and proteins, contemporarily enhancing AOA and, likely, sustaining normal activity of GPx. Thus, SkQ1 protects the retina from light-induced oxidative stress and could be employed to suppress oxidative damage of proteins and lipids contributing to AMD.

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

“…Photoreceptors and RPE cells generate high levels of ROS due to different factors: (i) the retina is a neuronal tissue characterized by extremely high oxygen consumption related to a highly demanding metabolism; (ii) photoreceptors are constantly exposed to light and contain several photosensitizer molecules; (iii) photoreceptor membranous disks are enriched in polyunsaturated fatty acids, which are particularly sensitive to oxidation damage; and (iv) the daily recycling of photoreceptor disks damaged by oxidative stress is performed via phagocytosis by RPE cells, and consequently, oxidative damage to photoreceptors induces accumulation of ROS in the RPE. Photooxidation causes lipofuscin accumulation, which is the oxidation byproduct of lipids and lipoproteins containing photo-oxidable fluorophores [15,16]. High levels of light-induced oxidative stress eventually triggers photoreceptor and inner retina apoptosis [17,18] and severely affects the phagocytic function of the RPE [19].…”

Mechanisms and Treatment of Light-Induced Retinal Degeneration-Associated Inflammation: Insights from Biochemical Profiling of the Aqueous Humor

“…The animals of the first group were subjected to the illumination without any subsequent treatment. In the second group, the animals were premedicated prior to the illumination with mitochondria-targeted antioxidant SkQ1, according to the method that was developed in our previous study [3]. The animals of the third group were treated for seven days after the illumination with Nepafenac, representing topical NSAID that is commonly used for the treatment of ocular inflammation [44].…”

“…Photoreceptor and RPE cells generate high levels of reactive oxygen species (ROS) due to constant exposure to light and the presence of multiple photosensitizer molecules. In addition, extremely high oxygen consumption and metabolic rates characterize the retina, which underlie its high susceptibility to mitochondrial oxidative stress [1,3].…”

“…LIRD also resembles retinal degenerative diseases in terms of the pathogenetic roles of oxidative stress and inflammation. Prolonged illumination of the retina with visible light induces photochemical reactions in photoreceptors and RPE cells, yielding an accumulation of ROS and the oxidation of lipids and proteins [3,14,15] characteristic to AMD and other degenerative retinopathies [8,16]. Furthermore, LIRD might induce breakage of the blood-retinal barrier thereby promoting leukocyte infiltration and macular edema [14,17], and these signs are also can be found in AMD patients [18,19].…”

“…Previously, we have developed a rabbit model of LIRD reproducing many aspects of AMD and other retinal degenerative diseases, such as apoptosis of photoreceptors and migration of RPE cells, as well as the breakdown of the blood-retinal barrier, leukocyte infiltration, edema, and other signs of intraocular inflammation [3,14,43]. These effects were accompanied by oxidative stress, which was efficiently prevented by premedication while using mitochondria-targeted antioxidant SkQ1 [3]. In the present study, we employed this model of LIRD to get insight into oxidative and inflammatory processes contributing to retinal degeneration diseases, such as AMD.…”