Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium.

A2E, an important constituent of lipofuscin in human retinal pigment epithelium (RPE), is thought to mediate light-induced oxidative damage associated with aging and other ocular disorders. Ocular carotenoids in overlying retinal tissues were measured by HPLC and mass spectrometry and were correlated with levels of RPE A2E. We observed a statistically significant increase in total A2E levels in human RPE/choroid with age, and A2E levels in macular regions were approximately 1/3 lower than in peripheral retinal regions of the same size. There was a statistically significant inverse correlation between peripheral retina carotenoids and peripheral RPE/choroid A2E. Prospective carotenoid supplementation studies in Japanese quail demonstrated nearly complete inhibition of A2E formation and oxidation. These findings support current recommendations to increase dietary intake of xanthophyll carotenoids in individuals at risk for macular degeneration and highlight a new potential mechanism for their protective effects-inhibition of A2E formation and oxidation in the eye.

[1]  Lawrence A. Yannuzzi,et al.  Dietary Carotenoids, Vitamins A, C, and E, and Advanced Age-Related Macular Degeneration , 1994 .

[2]  Koji Nakanishi,et al.  Photooxidation of A2-PE, a photoreceptor outer segment fluorophore, and protection by lutein and zeaxanthin. , 2006, Experimental eye research.

[3]  Werner Gellermann,et al.  Nonmydriatic fluorescence-based quantitative imaging of human macular pigment distributions. , 2006, Journal of the Optical Society of America. A, Optics, image science, and vision.

[4]  R. Radu,et al.  Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  K. Nakanishi,et al.  Rpe65 Leu450Met variant is associated with reduced levels of the retinal pigment epithelium lipofuscin fluorophores A2E and iso-A2E. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[6]  François C Delori,et al.  Autofluorescence method to measure macular pigment optical densities fluorometry and autofluorescence imaging. , 2004, Archives of biochemistry and biophysics.

[7]  M. Boulton,et al.  Blue light-induced singlet oxygen generation by retinal lipofuscin in non-polar media. , 1998, Free radical biology & medicine.

[8]  M. Boulton,et al.  The role of oxidative stress in the pathogenesis of age-related macular degeneration. , 2000, Survey of ophthalmology.

[9]  Y Zhao,et al.  Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  John D Simon,et al.  A2E: A Component of Ocular Lipofuscin¶ , 2004, Photochemistry and photobiology.

[11]  Jens Dreyhaupt,et al.  Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. , 2007, American journal of ophthalmology.

[12]  R. Allikmets,et al.  Small molecule RPE65 antagonists limit the visual cycle and prevent lipofuscin formation. , 2006, Biochemistry.

[13]  P. Bernstein,et al.  Identification of 3-methoxyzeaxanthin as a novel age-related carotenoid metabolite in the human macula. , 2007, Investigative ophthalmology & visual science.

[14]  K. Nakanishi,et al.  Characterization of Peroxy-A2E and Furan-A2E Photooxidation Products and Detection in Human and Mouse Retinal Pigment Epithelial Cell Lipofuscin* , 2005, Journal of Biological Chemistry.

[15]  P. Bernstein,et al.  Production of Deuterated Lutein by Chlorella protothecoides and its Detection by Mass Spectrometric Methods , 2006, Biotechnology Letters.

[16]  R. Bone,et al.  Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye. , 2003, Annual review of nutrition.

[17]  D. Bok,et al.  Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. , 2005, Investigative ophthalmology & visual science.

[18]  F. Ferris,et al.  The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. , 2007, Archives of ophthalmology.

[19]  K. Nakanishi,et al.  Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  George Britton,et al.  UV/Visible Spectroscopy , 1995 .

[21]  C. Wadelius,et al.  Enhanced accumulation of A2E in individuals homozygous or heterozygous for mutations in BEST1 (VMD2). , 2007, Experimental eye research.

[22]  M. Boulton,et al.  RPE lipofuscin and its role in retinal pathobiology. , 2005, Experimental eye research.

[23]  J. Weiter,et al.  Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. , 1989, Investigative ophthalmology & visual science.

[24]  P. Bernstein,et al.  HPLC measurement of ocular carotenoid levels in human donor eyes in the lutein supplementation era. , 2007, Investigative ophthalmology & visual science.

[25]  Werner Gellermann,et al.  Research Abstracts , 2022 .

[26]  Jeremy Nathans,et al.  Macular degeneration: recent advances and therapeutic opportunities , 2006, Nature Reviews Neuroscience.

[27]  J. Blumberg,et al.  The Potential Role of Dietary Xanthophylls in Cataract and Age-Related Macular Degeneration , 2000, Journal of the American College of Nutrition.

[28]  P. Sieving,et al.  Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  P. Bernstein,et al.  Identification and metabolic transformations of carotenoids in ocular tissues of the Japanese quail Coturnix japonica. , 2007, Biochemistry.

[30]  A. Langner,et al.  Effect of dietary zeaxanthin on tissue distribution of zeaxanthin and lutein in quail. , 2002, Investigative ophthalmology & visual science.

[31]  T. Sakmar,et al.  Interaction of A2E with Model Membranes. Implications to the Pathogenesis of Age-related Macular Degeneration , 2002, The Journal of general physiology.

[32]  D. Birch,et al.  Delayed dark-adaptation and lipofuscin accumulation in abcr+/- mice: implications for involvement of ABCR in age-related macular degeneration. , 2001, Investigative ophthalmology & visual science.

[33]  G. Travis,et al.  Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Koji Nakanishi,et al.  Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE. , 2002, Investigative ophthalmology & visual science.

[35]  P. Bernstein,et al.  Production of Deuterated Zeaxanthin by Flavobacterium Multivorum and its Detection by Resonance Raman and Mass Spectrometric Methods , 2005, Biotechnology Letters.