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

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.

Genomic-Metabolomic Associations Support the Role of LIPC and Glycerophospholipids in Age-Related Macular Degeneration

“… 38 Indeed, a recent metabolomics study in human donor eyes described significant differences in PE metabolites (and other glycerophospholipids) in eyes with AMD compared with healthy eyes. 39 A complete understanding of the role of glycerophospholipids (and lipids in general) in AMD pathogenesis remains lacking, 40 but as shown, met-QTL may provide insights into these relationships.…”

Genome-Wide Transcriptomic Analysis Identifies Pathways Regulated by Sterculic Acid in Retinal Pigmented Epithelium Cells

“…Nevertheless, high intensity injuries usually promote cell death through regulated or unregulated mechanisms such as apoptosis, necrosis, ferroptosis, pyroptosis, necroptosis, parthanatos, entosis or autopahagy [2,3]. The retina, like other tissues, must respond to environmental stimuli such as toxins, oxidative stress, inflammation, high metabolic activity or light-phototoxicity, which can induce deleterious effects over these Retinal Pigment Epithelium (RPE) cells [4,5]. Survival or death pathways activate depending on the stimuli, its intensity or the induced signaling.…”

Urinary Mass Spectrometry Profiles in Age-Related Macular Degeneration

“…In particular, they are thought to be involved in the transport of visual pigments. All our work to date on MS metabolomics of AMD has consistently shown differences in the glycerophospholipid pathway [18], and a recent study in human donor eyes also described significant differences in PE metabolites in eyes with AMD compared to controls [38].…”