Abstract
The benefits of antioxidant therapy for treating age-related macular degeneration, a devastating retinal disease, are limited. Perhaps species other than reactive oxygen intermediates should be considered as therapeutic targets. These could be lipid peroxidation products, including isolevuglandins (isoLGs), prototypical and extraordinarily reactive γ-ketoaldehydes that avidly bind to proteins, phospholipids, and DNA and modulate the properties of these biomolecules. We found isoLG adducts in aged human retina but not in the retina of mice kept under dim lighting. Hence, to test whether scavenging of isoLGs could complement or supplant antioxidant therapy, we exposed mice to bright light and found that this insult leads to retinal isoLG-adduct formation. We then pretreated mice with pyridoxamine, a B6 vitamer and efficient scavenger of γ-ketoaldehydes, and found that the levels of retinal isoLG adducts are decreased, and morphological changes in photoreceptor mitochondria are not as pronounced as in untreated animals. Our study demonstrates that preventing the damage to biomolecules by lipid peroxidation products, a novel concept in vision research, is a viable strategy to combat oxidative stress in the retina.
Highlights
Current antioxidant therapies do not directly target lipid peroxidation products
Mouse Model—IsoLG adducts were not found in the retina of mice kept under standard, i.e. dim (ϳ10 lux), lighting conditions as indicated by immunohistochemistry staining of their retinal cross-sections treated with the nonimmunized serum (N.I.) (Fig. 3A) and antiserum against iso[4]LGE2 as a representative isoLG isomer (Fig. 3B)
We found that one-time exposure to a 10,000 lux-light source for 2 h leads to a faint staining for iso[4]LGE2 (Fig. 3, E and F)
Summary
Current antioxidant therapies do not directly target lipid peroxidation products. Results: Pyridoxamine treatment scavenges lipid peroxides in mouse retina, as exemplified by isolevuglandins, and improves retinal mitochondrial morphology after animal exposure to bright light. General antioxidant therapies utilizing nutritional supplements, e.g. vitamins E and C and -carotene, have shown only low to moderate success in preventing cardiovascular events [36, 37], decreasing the risk of developing Alzheimer disease [38], and preventing the progression of intermediate to severe forms of AMD [39, 40]. This suggests that the first step in the oxidative injury cascade, i.e. the production of reactive oxygen intermediates (Fig. 1), is not sufficiently blocked. We developed a quantitative mass spectrometry (MS) assay for the measurements of the protein modification by isoLGs in retinal tissue and showed that treatment with PM followed by exposure to bright light decreases retinal isoLG adduction and lessens light-induced retinal pathologies
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