Abstract
Ocular inflammation contributes to the pathogenesis of blind-causing retinal degenerative diseases, such as age-related macular degeneration (AMD) or photic maculopathy. Here, we report on inflammatory mechanisms that are associated with retinal degeneration induced by bright visible light, which were revealed while using a rabbit model. Histologically and electrophysiologically noticeable degeneration of the retina is preceded and accompanied by oxidative stress and inflammation, as evidenced by granulocyte infiltration and edema in this tissue, as well as the upregulation of total protein, pro-inflammatory cytokines, and oxidative stress markers in aqueous humor (AH). Consistently, quantitative lipidomic studies of AH elucidated increase in the concentration of arachidonic (AA) and docosahexaenoic (DHA) acids and lyso-platelet activating factor (lyso-PAF), together with pronounced oxidative and inflammatory alterations in content of lipid mediators oxylipins. These alterations include long-term elevation of prostaglandins, which are synthesized from AA via cyclooxygenase-dependent pathways, as well as a short burst of linoleic acid derivatives that can be produced by both enzymatic and non-enzymatic free radical-dependent mechanisms. The upregulation of all oxylipins is inhibited by the premedication of the eyes while using mitochondria-targeted antioxidant SkQ1, whereas the accumulation of prostaglandins and lyso-PAF can be specifically suppressed by topical treatment with cyclooxygenase inhibitor Nepafenac. Interestingly, the most prominent antioxidant and anti-inflammatory benefits and overall retinal protective effects are achieved by simultaneous administrating of both drugs indicating their synergistic action. Taken together, these findings provide a rationale for using a combination of mitochondria-targeted antioxidant and cyclooxygenase inhibitor for the treatment of inflammatory components of retinal degenerative diseases.
Highlights
Inflammation is implicated in the etiology and progression of a number of blind-causing retinal degenerative diseases
We ascertained the mechanisms of intraocular inflammation associated with Light-induced retinal degeneration (LIRD) in the rabbit model
LIRD manifested as apoptosis of photoreceptors and other retinal neurons, as well as the vacuolization of retinal pigment epithelium (RPE) cells, their phagocytic activity, and migration into the neural retina
Summary
Inflammation is implicated in the etiology and progression of a number of blind-causing retinal degenerative diseases. The retina represents an immune-privileged zone that is separated by the inner and outer blood-retinal barriers that formed by retinal pigment epithelium (RPE) cells and microvascular endothelial cells, respectively [1,2]. Retinal degenerative conditions associated with environmental, age-related, vascular, metabolic, and/or genetic factors may deteriorate these barriers and, thereby, contribute to the propagation of intraocular inflammation affecting the retina [1]. Oxidative stress plays a critical role in triggering retinal degeneration and intraocular inflammation. 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. Extremely high oxygen consumption and metabolic rates characterize the retina, which underlie its high susceptibility to mitochondrial oxidative stress [1,3]
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