8-hydroxy-2--deoxyguanosine and Macular-Degeneration

An imbalance between the production of reactive oxygen species (ROS) and anti-oxidant capacity results in oxidative injury to cellular components and molecules, which in turn disturbs the homeostasis of cells and organs. Although retinitis pigmentosa (RP) is a hereditary disease, non-genetic biological factors including oxidative stress also modulate or contribute to the disease progression. In animal models of RP, the degenerating retina exhibits marked oxidative damage in the nucleic acids, proteins, and lipids, and anti-oxidant treatments substantially suppress photoreceptor cell death and microgliosis. Although the mechanisms by which oxidative stress mediates retinal degeneration have not been fully elucidated, our group has shown that oxidative DNA damage and its defense system are key regulators of microglial activation and photoreceptor degeneration in RP. In this review, we summarize the current evidence regarding oxidative stress in animal models and patients with RP. The clinical efficacy of anti-oxidant treatments for RP has not been fully established. Nevertheless, elucidating key biological processes that underlie oxidative damage in RP will be pivotal to understanding the pathology and developing a potent anti-oxidant strategy that targets specific cell types or molecules under oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Catalase; Disease Models, Animal; DNA Damage; DNA Glycosylases; DNA Repair Enzymes; Gene Expression Regulation; Glutathione Peroxidase; Humans; Macular Degeneration; Microglia; Oxidative Stress; Phosphoric Monoester Hydrolases; Reactive Oxygen Species; Retina; Retinitis Pigmentosa; Superoxide Dismutase

Age-related macular degeneration (AMD) is a multifactorial disease of the retina featured by dysfunction of retinal pigmented epithelial (RPE) and loss of photoreceptor cells under oxidative stress and inflammatory conditions. Vitamin D and antioxidants have beneficial effects against retinal degenerative diseases, such as AMD. We investigated the impact of associating vitamin D (ND) with a nutritional antioxidant complex (Nutrof Total

Topics: 8-Hydroxy-2'-Deoxyguanosine; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Cell Line; Cell Proliferation; Cytokines; Endothelial Cells; Humans; Macular Degeneration; Oxidation-Reduction; Oxidative Stress; Retinal Pigment Epithelium; Vitamin D

Age-related macular degeneration (AMD) is the leading cause of blindness among older adults in the developed world. Oxidative damage to mitochondrial DNA (mtDNA) in the retinal pigment epithelium (RPE) may play a key role in AMD. Measurement of oxidative DNA lesions such as 8-oxo-2'-deoxyguanosine (8-oxo-dG) and 8-oxo-2'-deoxyadenosine (8-oxo-dA) in diseased RPE could provide important insights into the mechanism of AMD development. We have developed a liquid chromatography-nanoelectrospray ionization-tandem mass spectrometry method for simultaneous analysis of 8-oxo-dG and 8-oxo-dA in human retinal DNA. The developed method was applied to the analysis of retinal DNA from 5 donors with AMD and 5 control donors without AMD. In mtDNA, the levels of 8-oxo-dG in controls and AMD donors averaged 170 and 188, and 8-oxo-dA averaged 11 and 17 adducts per 10(6) bases, respectively. In nuclear DNA, the levels of 8-oxo-dG in controls and AMD donors averaged 0.54 and 0.96, and 8-oxo-dA averaged 0.04 and 0.05 adducts per 10(6) bases, respectively. This highly sensitive method allows for the measurement of both adducts in very small amounts of DNA and can be used in future studies investigating the pathophysiological role of 8-oxo-dG and 8-oxo-dA in AMD and other oxidative damage-related diseases in humans.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Chromatography, Liquid; Deoxyadenosines; Deoxyguanosine; DNA Damage; DNA, Mitochondrial; Humans; Macular Degeneration; Molecular Structure; Nanotechnology; Reproducibility of Results; Retinal Pigment Epithelium; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Dietary carotenoids exhibit various biological activities, including antioxidative activity. In particular, astaxanthin, a type of carotenoid, is well known as a powerful antioxidant. We investigated whether astaxanthin would protect against light-induced retinal damage. In an in vivo study, ddY male mice were exposed to white light at 8,000 lux for 3 h to induce retinal damage. Five days after light exposure, retinal damage was evaluated by measuring electroretinogram (ERG) amplitude and outer nuclear layer (ONL) thickness. Furthermore, expression of apoptotic cells, 8-hydroxy-deoxyguanosine (8-OHdG), was measured. In an in vitro study, retinal damage was induced by white light exposure at 2,500 lux for 24 h, and propidium iodide (PI)-positive cells was measured and intracellular reactive oxygen species (ROS) activity was examined. Astaxanthin at 100 mg/kg inhibited the retinal dysfunction in terms of ERG and ONL loss and reduced the expression of apoptotic and 8-OHdG-positive cells induced by light exposure. Furthermore, astaxanthin protected against increases of PI-positive cells and intracellular reactive oxygen species (ROS) activity in 661W cells. These findings suggest that astaxanthin has protective effects against light-induced retinal damage via the mechanism of its antioxidative effect.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Ophthalmic; Animals; Antioxidants; Apoptosis; Cells, Cultured; Deoxyguanosine; Disease Models, Animal; Electroretinography; Light; Macular Degeneration; Male; Mice; Mice, Inbred Strains; Propidium; Reactive Oxygen Species; Retina; Retinal Cone Photoreceptor Cells; Retinitis Pigmentosa; Xanthophylls

Oxidative stress has been implicated as a major contributor to age-related macular degeneration (AMD). 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidative products of DNA damage and represents a noninvasive and sensitive biomarker of oxidative stress. The authors investigated the 8-OHdG levels in aqueous humor of patients with exudative AMD.. Twenty-four eyes of 24 patients with active exudative AMD and 31 eyes of 31 age-matched subjects who underwent cataract surgery were enrolled. Aqueous humor samples were collected from all subjects, and the 8-OHdG levels were determined by a commercially available enzyme-linked immunosorbent assay kit. The choroidal neovascularization (CNV) subtype was classified by fluorescein angiography. The macular lesion, including CNV membrane, exudation, and retinal hemorrhage, was measured. The correlation between 8-OHdG level and the clinical features was analyzed.. The 8-OHdG level in the aqueous humor of AMD patients was significantly higher than it was in controls (0.581 ± 0.258 ng/mL vs. 0.251 ± 0.116 ng/mL; P < 0.001), after adjusting for age and lens status. There was no difference in the 8-OHdG levels between AMD patients with classic/predominantly classic and occult/minimally classic CNV (0.591 ± 0.262 vs. 0.566 ± 0.266 ng/mL; P = 0.639). The 8-OHdG level in aqueous humor was significantly correlated with the lesion size (ρ = 0.492; P = 0.017).. The 8-OHdG level in aqueous humor was higher in patients with exudative AMD, and the level was correlated with the area of macular lesion. This suggests that oxidative stress plays an important role in the disease course of AMD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Aqueous Humor; Cataract Extraction; Choroidal Neovascularization; Deoxyguanosine; DNA Damage; Enzyme-Linked Immunosorbent Assay; Exudates and Transudates; Female; Humans; Macular Degeneration; Male; Oxidative Stress; Prospective Studies

To evaluate oxidative damage to the macromolecules, including protein, lipid, and DNA, in association with total oxidation status (TOS), total antioxidant capacity (TAC) in patients with exudative age-related macular degeneration (AMD).. Serum levels of malondialdehyde (MDA) as an index of lipid peroxidation, protein carbonyl (PC) as a marker of protein oxidation, 8-hydroxy-29-deoxyguanosine (8-OHdG) as an indicator of oxidative DNA damage along with TOS, TAC were measured by specific methods in 47 patients with exudative AMD and 25 age- and sex-matched healthy subjects.. Significantly higher MDA, PC, 8-OHdG, TOS, and lower TAC levels were detected in the serum of patients with exudative AMD compared with their controls (p < 0.001).. The results indicate that an imbalance between TOS and TAC leads to not only increased lipid damage, but also protein and DNA damage. These first reported results suggest that protein and DNA damage might also play a role in the pathogenesis of AMD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Antioxidants; Deoxyguanosine; Female; Humans; Macromolecular Substances; Macular Degeneration; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Protein Carbonylation