The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration

Abstract

Abstract. Age-related macular degeneration (AMD) is the leading cause of blind registration in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress and that the antioxidant vitamins A, C, and E protect against this type of injury. Furthermore, there is strong evidence suggesting that lipofuscin is derived, at least in part, from oxidatively damaged photoreceptor outer segments and that it is itself a photoreactive substance. However, the relationships between dietary and serum levels of the antioxidant vitamins and age-related macular disease are less clear, although a protective effect of high plasma concentrations of ␣ -tocopherol has been convincingly demonstrated. Macular pigment is also believed to limit retinal oxidative damage by absorbing incoming blue light and/or quenching ROIs. Many putative risk-factors for AMD have been linked to a lack of macular pigment, including female gender, lens density, tobacco use, light iris color, and reduced visual sensitivity. Moreover, the Eye Disease Case-Control Study found that high plasma levels of lutein and zeaxanthin were associated with reduced risk of neovascular AMD. The concept that AMD can be attributed to cumulative oxidative stress is enticing, but remains unproven. With a view to reducing oxidative damage, the effect of nutritional antioxidant supplements on the onset and natural course of age-related macular disease is currently being evaluated. Age-related macular degeneration (AMD) is the leading cause of blind registration in the western world, 119 and its prevalence is likely to rise as a consequence of increasing longevity. 225 There is a general consensus that cumulative oxidative damage is responsible for aging, and may, therefore, play an important role in the pathogenesis of AMD. In this article, we review the literature germane to oxidative processes in the retina and examine the evidence for a causal link between oxidative stress and age-related macular degeneration.

Resonance Raman measurement of macular carotenoids in normal subjects and in age-related macular degeneration patients

“…Moreover, AMD patients who have begun taking high-dose lutein supplements after initial diagnosis of AMD have normal levels of macular carotenoid pigment. These results taken together are very supportive of a model in which low macular levels of lutein and zeaxanthin represent a pathogenic risk factor for development of AMD, [1][2][3]6,7,19 presumably through decreased blue light screening or inadequate free radical quenching capacity. The apparent response to dietary supplementation implies that the carotenoid binding sites 37 in the macula are not saturated with lutein and zeaxanthin in many AMD patients consuming an unsupplemented diet.…”

“…[1][2][3] These compounds, derived from dietary intake of dark green leafy vegetables and orange or yellow fruits and vegetables, are specifically concentrated in the Henle fiber layer of the macula of the human eye, 4,5 where they may act to protect against light-induced oxidative damage through their ability to absorb phototoxic blue light and to quench free radicals. 6,7 Dietary supplementation with foods or supplements rich in lutein or zeaxanthin can raise macular pigment levels, 8 -10 and nutritional supplements containing lutein are promoted actively by the health food and vitamin industry in the United States to individuals at risk for AMD. Zeaxanthin supplements, however, were not commercially available in the United States until recently except as a minor component of lutein prepared from marigold flowers, and it has been suggested that dietary lutein may serve as a precursor for the very high concentrations of zeaxanthin found in the primate fovea.…”

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

“…One biologically plausible rationale for this finding rests on the fact that homozygosity for the CFH risk alleles is associated with unregulated inflammation and, therefore, excessive production of ROIs and a consequential depletion of local antioxidants, including the macular carotenoids. Similarly, increased risk associated with ARMS2 through mitochondrial dysfunction in the photoreceptor outer segments may result in failure to regulate or compartmentalize ROIs generated in these organelles by the respiratory chain (Beatty et al, 2000), with a consequential depletion of local antioxidants, such as L and Z. Moreover, such a failure to compartmentalize mitochondrially-generated ROIs will promote inflammatory changes with subsequent further ROI production, thus representing a self-perpetuating cascade of ROI production and inflammatory processes.…”

The complement system and age-related macular degeneration

“…31 Oxidative stress results in the activation and deposition of complement on the vascular endothelium. It is still unclear which specific complement pathways are involved in the primary mechanism of initial complement activation in oxidative stress.…”