Oxidation and age-related macular degeneration: insights from molecular biology

Sam Khandhadia; Andrew Lotery

doi:10.1017/S146239941000164X

Oxidation and age-related macular degeneration: insights from molecular biology

Published online by Cambridge University Press: 20 October 2010

Sam Khandhadia and

Andrew Lotery

Show author details

Sam Khandhadia: Affiliation:
Clinical Neurosciences Division, School of Medicine, University of Southampton, UK.
Andrew Lotery*: Affiliation:
Clinical Neurosciences Division, School of Medicine, University of Southampton, UK. Southampton General Hospital, Southampton, UK.
*: *Corresponding author: Andrew Lotery, Administrative Office, LD74, Clinical Neurosciences, South Lab & Path Block, Southampton General Hospital, Southampton SO16 6YD, UK. E-mail: [email protected]

Article contents

Abstract
References

Get access

Rights & Permissions

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. It is a multifactorial disease, and current therapy predominantly limits damage only when it has already occurred. The macula is a source of high metabolic activity, and is therefore exposed to correspondingly high levels of reactive oxygen species (ROS). With age, the balance between production of ROS and local antioxidant levels is shifted, and damage ensues. Systemic ROS and antioxidant levels in AMD reflect these local processes. Genetic studies investigating mutations in antioxidant genes in AMD are inconclusive and further studies are indicated, especially to determine the role of mitochondria. Oral antioxidant supplements could be beneficial, and diet modification may help. Future treatments might either increase antioxidant capacity or reduce the production of ROS, using methods such as genetic manipulation. This article reviews the role of oxidative stress in AMD and the potential therapies that might have a role in preventing the blindness resulting from this disease.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e34

DOI: https://doi.org/10.1017/S146239941000164X [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Resnikoff, S. et al. (2004) Global data on visual impairment in the year 2002. Bulletin of the World Health Organization 82, 844-851Google Scholar

2de Jong, P.T.V.M. (2006) Age-related macular degeneration. New England Journal of Medicine 355, 1474-1485CrossRef Google Scholar PubMed

3Friedman, D.S. et al. (2004) Prevalence of age-related macular degeneration in the United States. Archives of Ophthalmology 122, 564-572Google Scholar PubMed

4Brown, D.M. et al. (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. New England Journal of Medicine 355, 1432-1444CrossRef Google Scholar PubMed

5Rosenfeld, P.J. et al. (2006) Ranibizumab for neovascular age-related macular degeneration. New England Journal of Medicine 355, 1419-1431Google Scholar

6Schmitz-Valckenberg, S. et al. (2010) Combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging of reticular drusen associated with age related macular degeneration. Ophthalmology 117, 1169-1176Google Scholar

7Klein, R. et al. (2008) The epidemiology of retinal reticular drusen. American Journal of Ophthalmology 145, 317-326CrossRef Google Scholar PubMed

8Knudtson, M.D. et al. (2004) Location of lesions associated with age-related maculopathy over a 10-year period: the Beaver Dam Eye Study. Investigative Ophthalmology and Visual Science 45, 2135-2142CrossRef Google Scholar

9Lotery, A. and Trump, D. (2007) Progress in defining the molecular biology of age related macular degeneration. Human Genetics 122, 219-236CrossRef Google Scholar PubMed

10Augood, C.A. et al. (2006) Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE). Archives of Ophthalmology 124, 529-535Google Scholar

11Muller, F.L. et al. (2007) Trends in oxidative aging theories. Free Radical Biology and Medicine 43, 477-503Google Scholar

12Chance, B., Sies, H. and Boveris, A. (1979) Hydroperoxide metabolism in mammalian organs. Physiological Reviews 59, 527-605CrossRef Google Scholar PubMed

13Golden, T.R. and Melov, S. (2001) Mitochondrial DNA mutations, oxidative stress, and aging. Mechanisms of Ageing and Development 122, 1577-1589Google Scholar

14Hayflick, L. and Moorhead, P.S. (1961) The serial cultivation of human diploid cell strains. Experimental Cell Research 25, 585-621CrossRef Google Scholar PubMed

15Yuan, H., Kaneko, T. and Matsuo, M. (1995) Relevance of oxidative stress to the limited replicative capacity of cultured human diploid cells: the limit of cumulative population doublings increases under low concentrations of oxygen and decreases in response to aminotriazole. Mechanisms of Ageing and Development 81, 159-168CrossRef Google Scholar

16Adelfalk, C. et al. (2001) Accelerated telomere shortening in Fanconi anemia fibroblasts–a longitudinal study. FEBS Letters 506, 22-26CrossRef Google Scholar PubMed

17Rubio, M.A., Davalos, A.R. and Campisi, J. (2004) Telomere length mediates the effects of telomerase on the cellular response to genotoxic stress. Experimental Cell Research 298, 17-27CrossRef Google Scholar PubMed

18Ballinger, S.W. et al. (1999) Hydrogen peroxide causes significant mitochondrial DNA damage in human RPE cells. Experimental Eye Research 68, 765-772Google Scholar

19Cai, J. et al. (2000) Oxidative damage and protection of the RPE. [Review] [138 Refs]. Progress in Retinal and Eye Research 19, 205-221CrossRef Google Scholar

20Susin, S.A. et al. (1999) Mitochondrial release of caspase-2 and -9 during the apoptotic process. Journal of Experimental Medicine 189, 381-394CrossRef Google Scholar PubMed

21Yang, J. et al. (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129-1132Google Scholar

22Lundberg, W.O. (1958) Lipids of biologic importance; peroxidation products and inclusion compounds of lipids. American Journal of Clinical Nutrition 6, 601-603CrossRef Google Scholar PubMed

23Harman, D. (1956) Aging: a theory based on free radical and radiation chemistry. Journal of Gerontology 11, 298-300Google Scholar

24Organisciak, D.T. et al. (1998) Light history and age-related changes in retinal light damage. Investigative Ophthalmology and Visual Science 39, 1107-1116Google Scholar

25Yamashita, H. et al. (1992) Light-induced retinal damage in mice. Hydrogen peroxide production and superoxide dismutase activity in retina. Retina 12, 59-66Google Scholar

26van Kuijk, F.J. and Buck, P. (1992) Fatty acid composition of the human macula and peripheral retina. Investigative Ophthalmology and Visual Science 33, 3493-3496Google Scholar

27Roehlecke, C. et al. (2009) The influence of sublethal blue light exposure on human RPE cells. Molecular Vision 15, 1929-1938Google Scholar

28Miceli, M.V., Liles, M.R. and Newsome, D.A. (1994) Evaluation of oxidative processes in human pigment epithelial cells associated with retinal outer segment phagocytosis. Experimental Cell Research 214, 242-249CrossRef Google Scholar PubMed

29Jiang, S. et al. (2005) Oxidant-induced apoptosis in human retinal pigment epithelial cells: dependence on extracellular redox state. Investigative Ophthalmology and Visual Science 46, 1054-1061CrossRef Google Scholar PubMed

30Glotin, A.L. et al. (2008) Prematurely senescent ARPE-19 cells display features of age-related macular degeneration. Free Radical Biology and Medicine 44, 1348-1361Google Scholar

31Yu, A.L. et al. (2009) Subtoxic oxidative stress induces senescence in retinal pigment epithelial cells via TGF-beta release. Investigative Ophthalmology and Visual Science 50, 926-935CrossRef Google Scholar PubMed

32Sanvicens, N. et al. (2004) Oxidative stress-induced apoptosis in retinal photoreceptor cells is mediated by calpains and caspases and blocked by the oxygen radical scavenger CR-6. Journal of Biological Chemistry 279, 39268-39278Google Scholar

33Fuchshofer, R. et al. (2009) Hypoxia/reoxygenation induces CTGF and PAI-1 in cultured human retinal pigment epithelium cells. Experimental Eye Research 88, 889-899Google Scholar

34Pemp, B. et al. (2010) Effects of antioxidants (AREDS medication) on ocular blood flow and endothelial function in an endotoxin-induced model of oxidative stress in humans. Investigative Ophthalmology and Visual Science 51, 2-6Google Scholar

35Gottsch, J.D. et al. (1990) Hematogenous photosensitization. A mechanism for the development of age-related macular degeneration. Investigative Ophthalmology and Visual Science 31, 1674-1682Google Scholar PubMed

36Yang, D. et al. (2009) Association of superoxide anions with retinal pigment epithelial cell apoptosis induced by mononuclear phagocytes. Investigative Ophthalmology and Visual Science 50, 4998-5005Google Scholar

37Chen, M., Forrester, J.V. and Xu, H. (2007) Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Experimental Eye Research 84, 635-645Google Scholar

38Thurman, J.M. et al. (2009) Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. Journal of Biological Chemistry 284, 16939-16947Google Scholar

39Hollyfield, J.G. et al. (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nature Medicine 14, 194-198Google Scholar

40Zhang, B. et al. (2009) Anti-inflammatory and antioxidant effects of SERPINA3 K in the retina. Investigative Ophthalmology and Visual Science 50, 3943-3952Google Scholar

41Kliffen, M. et al. (1997) Increased expression of angiogenic growth factors in age-related maculopathy. British Journal of Ophthalmology 81, 154-162Google Scholar

42Kannan, R. et al. (2006) Stimulation of apical and basolateral VEGF-A and VEGF-C secretion by oxidative stress in polarized retinal pigment epithelial cells. Molecular Vision 12, 1649-1659Google Scholar

43Sari, A. et al. (2009) Effects of intravitreal bevacizumab in repeated doses: an experimental study. Retina 29, 1346-1355CrossRef Google Scholar PubMed

44Young, A.J. and Lowe, G.M. (2001) Antioxidant and prooxidant properties of carotenoids. Archives of Biochemistry and Biophysics 385, 20-27Google Scholar

45Packer, L. (1993) Antioxidant action of carotenoids in vitro and in vivo and protection against oxidation of human low-density lipoproteins. Annal of the New York Academy of Sciences 691, 48-60CrossRef Google Scholar PubMed

46Lim, B.P. et al. (1992) Antioxidant activity of xanthophylls on peroxyl radical-mediated phospholipid peroxidation. Biochimica et Biophysica Acta 1126, 178-184Google Scholar

47Chucair, A.J. et al. (2007) Lutein and zeaxanthin protect photoreceptors from apoptosis induced by oxidative stress: relation with docosahexaenoic acid. Investigative Ophthalmology and Visual Science 48, 5168-5177CrossRef Google Scholar PubMed

48Nakajima, Y. et al. (2009) Zeaxanthin, a retinal carotenoid, protects retinal cells against oxidative stress. Current Eye Research 34, 311-318Google Scholar

49Lakshminarayana, R. et al. (2008) Possible degradation/biotransformation of lutein in vitro and in vivo: isolation and structural elucidation of lutein metabolites by HPLC and LC-MS (atmospheric pressure chemical ionization). Free Radical Biology and Medicine 45, 982-993Google Scholar

50Khachik, F., Bernstein, P.S. and Garland, D.L. (1997) Identification of lutein and zeaxanthin oxidation products in human and monkey retinas. Investigative Ophthalmology and Visual Science 38, 1802-1811Google Scholar

51Behndig, A. et al. (1998) Superoxide dismutase isoenzymes in the human eye. Investigative Ophthalmology and Visual Science 39, 471-475Google Scholar

52Liles, M.R., Newsome, D.A. and Oliver, P.D. (1991) Antioxidant enzymes in the aging human retinal pigment epithelium. Archives of Ophthalmology 109, 1285-1288Google Scholar

53Sreekumar, P.G. et al. (2005) Protection from oxidative stress by methionine sulfoxide reductases in RPE cells. Biochemical and Biophysical Research Communications 334, 245-253CrossRef Google Scholar PubMed

54Kutty, R.K. et al. (1995) Induction of heme oxygenase 1 in the retina by intense visible light: suppression by the antioxidant dimethylthiourea. Proceedings of the National Academy of Sciences of the United States of America 92, 1177-1181CrossRef Google Scholar PubMed

55Melo, P. et al. (2010) Oxidative stress response in the adult rat retina and plasma after repeated administration of methamphetamine. Neurochemistry International 56, 431-436Google Scholar

56Peters, S. et al. (2006) Melanin protects choroidal blood vessels against light toxicity. Zeitschrift fur Naturforschung Section C Journal of Biosciences 61, 427-433CrossRef Google Scholar PubMed

57Liang, F.Q. et al. (2004) Melatonin protects human retinal pigment epithelial (RPE) cells against oxidative stress. Experimental Eye Research 78, 1069-1075Google Scholar

58Ryan, S.J. (2006) Retina (4th edn), Elsevier/Mosby, Philadelphia, PA, USAGoogle Scholar

59Iwasaki, M. and Inomata, H. (1988) Lipofuscin granules in human photoreceptor cells. Investigative Ophthalmology and Visual Science 29, 671-679Google Scholar

60Ng, K.P. et al. (2008) Retinal pigment epithelium lipofuscin proteomics. Molecular and Cellular Proteomics 7, 1397-1405Google Scholar

61Nilsson, S.E. et al. (2003) Aging of cultured retinal pigment epithelial cells: oxidative reactions, lipofuscin formation and blue light damage. Documenta Ophthalmologica 106, 13-16CrossRef Google Scholar PubMed

62Wassell, J. et al. (1999) The photoreactivity of the retinal age pigment lipofuscin. Journal of Biological Chemistry 274, 23828-23832Google Scholar

63Ng, K.P. et al. (2008) Retinal pigment epithelium lipofuscin proteomics. Molecular and Cellular Proteomics 7, 1397-1405Google Scholar

64Schutt, F. et al. (2003) Proteins modified by malondialdehyde, 4-hydroxynonenal, or advanced glycation end products in lipofuscin of human retinal pigment epithelium. Investigative Ophthalmology and Visual Science 44, 3663-3668Google Scholar

65Shamsi, F.A. and Boulton, M. (2001) Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin. Investigative Ophthalmology and Visual Science 42, 3041-3046Google Scholar

66Sparrow, J.R. et al. (2003) A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation. Journal of Biological Chemistry 278, 18207-18213Google Scholar

67Sparrow, J.R., Nakanishi, K. and Parish, C.A. (2000) The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Investigative Ophthalmology and Visual Science 41, 1981-1989Google Scholar PubMed

68Sparrow, J.R. and Cai, B. (2001) Blue light-induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bcl-2. Investigative Ophthalmology and Visual Science 42, 1356-1362Google Scholar

69Zhou, J. et al. (2009) Complement activation by bisretinoid constituents of RPE lipofuscin. Investigative Ophthalmology and Visual Science 50, 1392-1399Google Scholar

70Wang, Z., Dillon, J. and Gaillard, E.R. (2006) Antioxidant properties of melanin in retinal pigment epithelial cells. Photochemistry and Photobiology 82, 474-479Google Scholar

71Castorina, C. et al. (1992) Lipid peroxidation and antioxidant enzymatic systems in rat retina as a function of age. Neurochemical Research 17, 599-604Google Scholar

72Zareba, M. et al. (2006) Effects of photodegradation on the physical and antioxidant properties of melanosomes isolated from retinal pigment epithelium. Photochemistry and Photobiology 82, 1024-1029Google Scholar

73Rozanowski, B. et al. (2008) The phototoxicity of aged human retinal melanosomes. Photochemistry and Photobiology 84, 650-657Google Scholar

74Feigl, B., Stewart, I. and Brown, B. (2007) Experimental hypoxia in human eyes: implications for ischaemic disease. Clinical Neurophysiology 118, 887-895Google Scholar

75Nork, T.M. et al. (2006) Measurement of regional choroidal blood flow in rabbits and monkeys using fluorescent microspheres. Archives of Ophthalmology 124, 860-868CrossRef Google Scholar PubMed

76Wing, G.L., Blanchard, G.C. and Weiter, J.J. (1978) The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Investigative Ophthalmology and Visual Science 17, 601-607Google Scholar

77Bone, R.A. et al. (1997) Distribution of lutein and zeaxanthin stereoisomers in the human retina. Experimental Eye Research 64, 211-218Google Scholar

78Rapp, L.M., Maple, S.S. and Choi, J.H. (2000) Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina. Investigative Ophthalmology and Visual Science 41, 1200-1209Google Scholar PubMed

79Bertram, K.M. et al. (2009) Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration. American Journal of Physiology – Cell Physiology 297, C1200-C1210CrossRef Google Scholar PubMed

80Jia, L. et al. (2007) Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-alpha-lipoic acid. Investigative Ophthalmology and Visual Science 48, 339-348Google Scholar

81Kalariya, N.M. et al. (2009) Cadmium-induced apoptotic death of human retinal pigment epithelial cells is mediated by MAPK pathway. Experimental Eye Research 89, 494-502CrossRef Google Scholar PubMed

82Klein, R. et al. (1993) The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. American Journal of Epidemiology 137, 190-200Google Scholar

83Smith, W., Mitchell, P. and Leeder, S.R. (1996) Smoking and age-related maculopathy. The Blue Mountains Eye Study. Archives of Ophthalmology 114, 1518-1523Google Scholar

84Vingerling, J.R. et al. (1996) Age-related macular degeneration and smoking. The Rotterdam Study. Archives of Ophthalmology 114, 1193-1196Google Scholar

85Tomany, S.C. et al. (2004) Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Study. Archives of Ophthalmology 122, 750-757Google Scholar

86West, S.K. et al. (1989) Exposure to sunlight and other risk factors for age-related macular degeneration. Archives of Ophthalmology 107, 875-879Google Scholar

87Taylor, H.R. et al. (1990) Visible light and risk of age-related macular degeneration. Transactions of the American Ophthalmological Society 88, 163-173Google Scholar

88Cruickshanks, K.J., Klein, R. and Klein, B.E. (1993) Sunlight and age-related macular degeneration. The Beaver Dam Eye Study. Archives of Ophthalmology 111, 514-518Google Scholar

89Darzins, P., Mitchell, P. and Heller, R.F. (1997) Sun exposure and age-related macular degeneration. An Australian case-control study. Ophthalmology 104, 770-776Google Scholar

90Fletcher, A.E. et al. (2008) Sunlight exposure, antioxidants, and age-related macular degeneration. Archives of Ophthalmology 126, 1396-1403CrossRef Google Scholar PubMed

91Bruban, J. et al. (2009) Amyloid-beta(1-42) alters structure and function of retinal pigmented epithelial cells. Aging Cell 8, 162-177Google Scholar

92Crabb, J.W. et al. (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 99, 14682-14687Google Scholar

93Frank, R.N., Amin, R.H. and Puklin, J.E. (1999) Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular age-related macular degeneration. American Journal of Ophthalmology 127, 694-709Google Scholar

94Decanini, A. et al. (2007) Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. American Journal of Ophthalmology 143, 607-615Google Scholar

95Totan, Y. et al. (2009) Oxidative macromolecular damage in age-related macular degeneration. Current Eye Research 34, 1089-1093Google Scholar

96Evereklioglu, C. et al. (2003) Nitric oxide and lipid peroxidation are increased and associated with decreased antioxidant enzyme activities in patients with age-related macular degeneration. Documenta Ophthalmologica 106, 129-136Google Scholar

97Totan, Y. et al. (2001) Plasma malondialdehyde and nitric oxide levels in age related macular degeneration. British Journal of Ophthalmology 85, 1426-1428Google Scholar

98Tsai, D.C. et al. (2006) Different plasma levels of vascular endothelial growth factor and nitric oxide between patients with choroidal and retinal neovascularization. Ophthalmologica 220, 246-251Google Scholar

99Rochtchina, E. et al. (2007) Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study. American Journal of Ophthalmology 143, 344-346Google Scholar

100Seddon, J.M. et al. (2006) Evaluation of plasma homocysteine and risk of age-related macular degeneration. American Journal of Ophthalmology 141, 201-203Google Scholar

101Coral, K. et al. (2006) Plasma homocysteine and total thiol content in patients with exudative age-related macular degeneration. Eye (London) 20, 203-207Google Scholar

102Ates, O. et al. (2009) Decreased serum paraoxonase 1 activity and increased serum homocysteine and malondialdehyde levels in age-related macular degeneration. Tohoku Journal of Experimental Medicine 217, 17-22Google Scholar

103Nowak, M. et al. (2005) Homocysteine, vitamin B12, and folic acid in age-related macular degeneration. European Journal of Ophthalmology 15, 764-767Google Scholar

104Vine, A.K. et al. (2005) Biomarkers of cardiovascular disease as risk factors for age-related macular degeneration. Ophthalmology 112, 2076-2080Google Scholar

105Kamburoglu, G. et al. (2006) Plasma homocysteine, vitamin B12 and folate levels in age-related macular degeneration. Graefes Archive for Clinical and Experimental Ophthalmology 244, 565-569Google Scholar

106Axer-Siegel, R. et al. (2004) Association of neovascular age-related macular degeneration and hyperhomocysteinemia. American Journal of Ophthalmology 137, 84-89Google Scholar

107Heuberger, R.A. et al. (2002) Relation of blood homocysteine and its nutritional determinants to age-related maculopathy in the third National Health and Nutrition Examination Survey. American Journal of Clinical Nutrition 76, 897-902Google Scholar

108Wu, K.H. et al. (2007) Circulating inflammatory markers and hemostatic factors in age-related maculopathy: a population-based case-control study. Investigative Ophthalmology and Visual Science 48, 1983-1988Google Scholar

109Eye Disease Case-Control Study Group. (1993) Antioxidant status and neovascular age-related macular degeneration. Archives of Ophthalmology 111, 104-109CrossRef Google Scholar

110Michikawa, T. et al. (2009) Serum antioxidants and age-related macular degeneration among older Japanese. Asia Pacific Journal of Clinical Nutrition 18, 1-7Google Scholar

111Mares-Perlman, J.A. et al. (1995) Serum antioxidants and age-related macular degeneration in a population-based case-control study. Archives of Ophthalmology 113, 1518-1523CrossRef Google Scholar

112Cardinault, N. et al. (2005) Lycopene but not lutein nor zeaxanthin decreases in serum and lipoproteins in age-related macular degeneration patients. Clinica Chimica Acta 357, 34-42Google Scholar

113Simonelli, F. et al. (2002) Serum oxidative and antioxidant parameters in a group of Italian patients with age-related maculopathy. Clinica Chimica Acta 320, 111-115CrossRef Google Scholar

114Prashar, S. et al. (1993) Antioxidant enzymes in RBCs as a biological index of age related macular degeneration. Acta Ophthalmologica 71, 214-218Google Scholar

115Yildirim, O. et al. (2004) Changes in antioxidant enzyme activity and malondialdehyde level in patients with age-related macular degeneration. Ophthalmologica 218, 202-206Google Scholar

116Cohen, S.M. et al. (1994) Low glutathione reductase and peroxidase activity in age-related macular degeneration. British Journal of Ophthalmology 78, 791-794Google Scholar

117Baskol, G. et al. (2006) Serum paraoxonase 1 activity and lipid peroxidation levels in patients with age-related macular degeneration. Ophthalmologica 220, 12-16Google Scholar

118De, LaPaz, M.A., Zhang, J. and Fridovich, I. (1996) Red blood cell antioxidant enzymes in age-related macular degeneration. British Journal of Ophthalmology 80, 445-450Google Scholar

119Delcourt, C. et al. (1999) Associations of antioxidant enzymes with cataract and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Ophthalmology 106, 215-222CrossRef Google Scholar PubMed

120Newsome, D.A. et al. (1986) Macular degeneration and elevated serum ceruloplasmin. Investigative Ophthalmology and Visual Science 27, 1675-1680Google Scholar

121Schmid-Kubista, K.E. et al. (2009) Daytime levels of melatonin in patients with age-related macular degeneration. Acta Ophthalmologica 87, 89-93Google Scholar

122Suzuki, M. et al. (2007) Oxidized phospholipids in the macula increase with age and in eyes with age-related macular degeneration. Molecular Vision 13, 772-778Google Scholar

123Choudhary, S. et al. (2005) Toxicity and detoxification of lipid-derived aldehydes in cultured retinal pigmented epithelial cells. Toxicology and Applied Pharmacology 204, 122-134Google Scholar

124Fliesler, S.J. and Anderson, R.E. (1983) Chemistry and metabolism of lipids in the vertebrate retina. Progress in Lipid Research 22, 79-131CrossRef Google Scholar PubMed

125Gu, X. et al. (2003) Oxidatively truncated docosahexaenoate phospholipids: total synthesis, generation, and peptide adduction chemistry. Journal of Organic Chemistry 68, 3749-3761Google Scholar

126Gu, X. et al. (2003) Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. Journal of Biological Chemistry 278, 42027-42035Google Scholar

127Ebrahem, Q. et al. (2006) Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: implications for age-related macular degeneration.[Erratum appears in Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15722]. Proceedings of the National Academy of Sciences of the United States of America 103, 13480-13484Google Scholar

128Gu, J. et al. (2009) Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers. Molecular and Cellular Proteomics 8, 1338-1349Google Scholar

129Ikeda, T. et al. (2001) Paraoxonase gene polymorphisms and plasma oxidized low-density lipoprotein level as possible risk factors for exudative age-related macular degeneration. American Journal of Ophthalmology 132, 191-195Google Scholar

130Javadzadeh, A. et al. (2007) Enhanced susceptibility of low-density lipoprotein to oxidation in wet type age-related macular degeneration in male patients. Saudi Medical Journal 28, 221-224Google Scholar

131Ethen, C.M. et al. (2007) Age-related macular degeneration and retinal protein modification by 4-hydroxy-2-nonenal. Investigative Ophthalmology and Visual Science 48, 3469-3479Google Scholar

132Johnson, F. and Giulivi, C. (2005) Superoxide dismutases and their impact upon human health. Molecular Aspects of Medicine 26, 340-352CrossRef Google Scholar PubMed

133Online Mendelian Inheritance in Man, OMIM (TM). McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD). World Wide Web URL:http://www.ncbi.nlm.nih.gov/omim/Google Scholar

134Kimura, K. et al. (2000) Genetic association of manganese superoxide dismutase with exudative age-related macular degeneration. American Journal of Ophthalmology 130, 769-773Google Scholar

135Gotoh, N. et al. (2008) Manganese superoxide dismutase gene (SOD2) polymorphism and exudative age-related macular degeneration in the Japanese population. American Journal of Ophthalmology 146, 146-147Google Scholar

136Kondo, N. et al. (2009) SOD2 gene polymorphisms in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Molecular Vision 15, 1819-1826Google Scholar PubMed

137Esfandiary, H. et al. (2005) Association study of detoxification genes in age related macular degeneration. British Journal of Ophthalmology 89, 470-474Google Scholar

138Dong, A. et al. (2009) Oxidative stress promotes ocular neovascularization. Journal of Cellular Physiology 219, 544-552Google Scholar

139Imamura, Y. et al. (2006) Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 103, 11282-11287Google Scholar

140Hashizume, K. et al. (2008) Retinal dysfunction and progressive retinal cell death in SOD1-deficient mice. American Journal of Pathology 172, 1325-1331Google Scholar

141Kasahara, E. et al. (2005) SOD2 protects against oxidation-induced apoptosis in mouse retinal pigment epithelium: implications for age-related macular degeneration. Investigative Ophthalmology and Visual Science 46, 3426-3434CrossRef Google Scholar PubMed

142Lu, L. et al. (2009) Increased expression of glutathione peroxidase 4 strongly protects retina from oxidative damage. Antioxidants and Redox Signaling 11, 715-724Google Scholar

143Jakobsdottir, J. et al. (2005) Susceptibility genes for age-related maculopathy on chromosome 10q26. American Journal of Human Genetics 77, 389-407Google Scholar

144Rivera, A. et al. (2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Human Molecular Genetics 14, 3227-3236Google Scholar

145Fritsche, L.G. et al. (2008) Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nature Genetics 40, 892-896Google Scholar

146Wang, G. et al. (2009) Localization of age-related macular degeneration-associated ARMS2 in cytosol, not mitochondria. Investigative Ophthalmology and Visual Science 50, 3084-3090Google Scholar

147Schmidt, S. et al. (2006) Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. American Journal of Human Genetics 78, 852-864Google Scholar

148Jones, M.M. et al. (2007) Mitochondrial DNA haplogroups and age-related maculopathy. Archives of Ophthalmology 125, 1235-1240Google Scholar

149SanGiovanni, J.P. et al. (2009) Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS One 4, e5508Google Scholar

150Swaroop, A. et al. (2009) Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. Annual Review of Genomics and Human Genetics 10, 19-43Google Scholar

151Klein, R.J. et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308, 385-389Google Scholar

152Haines, J.L. et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419-421Google Scholar

153Edwards, A.O. et al. (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308, 421-424Google Scholar

154Yates, J.R. et al. (2007) Complement C3 variant and the risk of age-related macular degeneration. New England Journal of Medicine 357, 553-561CrossRef Google Scholar PubMed

155Gold, B. et al. (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nature Genetics 38, 458-462Google Scholar

156Ennis, S. et al. (2009) Support for the involvement of complement factor I in age-related macular degeneration. European Journal of Human Genetics 18, 15-16Google Scholar

157Fagerness, J.A. et al. (2009) Variation near complement factor I is associated with risk of advanced AMD. European Journal of Human Genetics 17, 100-104CrossRef Google Scholar PubMed

158Hageman, G.S. et al. (2006) Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Annals of Medicine 38, 592-604Google Scholar

159Hughes, A.E. et al. (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nature Genetics 38, 1173-1177Google Scholar

160Ennis, S. et al. (2008) Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet 372, 1828-1834CrossRef Google Scholar PubMed

161Meyers, S.M., Ostrovsky, M.A. and Bonner, R.F. (1993) A model of spectral filtering to reduce photochemical damage in age-related macular degeneration. Transactions of the American Ophthalmological Society 102, 83-93Google Scholar

162Khan, J.C. et al. (2006) Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation. British Journal of Ophthalmology 90, 75-80Google Scholar

163Sundelin, S.P. and Nilsson, S.E. (2001) Lipofuscin-formation in retinal pigment epithelial cells is reduced by antioxidants. Free Radical Biology and Medicine 31, 217-225Google Scholar

164Chong, E.W. et al. (2007) Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis. BMJ 335, 755-758Google Scholar

165Age-Related Eye Disease Study Research Group. (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8 [Erratum appears in Arch Ophthalmol. 2008 Sep;126(9):1251]. Archives of Ophthalmology 119, 1417-1436Google Scholar

166 Vanderbilt University, USA. Antioxidant systems and age-related macular degeneration. In ClinicalTrials.gov [Internet], National Library of Medicine (US), Bethesda, MD, USA, 2000 [cited 2010 July 07], available from: http://clinicaltrials.gov/ct2/show/NCT00668213. NLM Identifier: NCT00668213Google Scholar

167Omenn, G.S. et al. (1996) Risk factors for lung cancer and for intervention effects in CARET, the beta-carotene and retinol efficacy trial. Journal of National Cancer Institute 88, 1550-1559Google Scholar

168National Eye Institute (NEI). Age-related eye disease study 2 (AREDS2). In ClinicalTrials.gov [Internet], National Library of Medicine (US), Bethesda, MD, USA, 2000 [cited 2010 March 20], available from: http://clinicaltrials.gov/ct2/show/NCT00345176. NLM Identifier: NCT00345176Google Scholar

169 Centre de Recherche en Nutrition Humaine Rhone-Alpe, France. Superoxide dismutase (SOD) as antioxidant treatment of age related macular degeneration (ARMD). In ClinicalTrials.gov [Internet], National Library of Medicine (US), Bethesda, MD, USA, 2000 [cited 2010 July 07], available from: http://clinicaltrials.gov/ct2/show/NCT00800995. NLM Identifier: NCT00800995Google Scholar

170Zhang, B. and Osborne, N.N. (2006) Oxidative-induced retinal degeneration is attenuated by epigallocatechin gallate. Brain Research 1124, 176-187Google Scholar

171 National Eye Institute (NEI), USA. Effects of antioxidants on human macular pigments. In ClinicalTrials.gov [Internet], National Library of Medicine (US), Bethesda, MD, USA, 2000 [cited 2010 July 07], available from http://clinicaltrials.gov/ct2/show/NCT00718653. NLM Identifier: NCT00718653Google Scholar

172Li, L. et al. (2010) Supplementation with lutein or lutein plus green tea extracts does not change oxidative stress in adequately nourished older adults. Journal of Nutritional Biochemistry 21, 544-549Google Scholar

173Singh, S. and Aggarwal, B.B. (1995) Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. Journal of Biological Chemistry 270, 24995-25000Google Scholar

174Scapagnini, G. et al. (2006) Curcumin activates defensive genes and protects neurons against oxidative stress. Antioxidants and Redox Signaling 8, 395-403Google Scholar

175Abe, Y., Hashimoto, S. and Horie, T. (1999) Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacological Research 39, 41-47Google Scholar

176Mandal, M.N. et al. (2009) Curcumin protects retinal cells from light-and oxidant stress-induced cell death. Free Radical Biology and Medicine 46, 672-679Google Scholar

177Dubey, A.K. et al. (2004) Ginkgo biloba – an appraisal. [Review] [44 Refs]. Kathmandu University Medical Journal 2, 225-229Google Scholar

178King, R.E., Kent, K.D. and Bomser, J.A. (2005) Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition. Chemico-Biological Interactions 151, 143-149Google Scholar

179Kumar, A. and Sharma, S.S. (2010) NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochemical and Biophysical Research Communications 394, 360-365CrossRef Google Scholar

180Kook, D. et al. (2008) The protective effect of quercetin against oxidative stress in the human RPE in vitro. Investigative Ophthalmology Visual Science 49, 1712-1720Google Scholar

181Wielgus, A.R. et al. (2007) Phototoxicity in human retinal pigment epithelial cells promoted by hypericin, a component of St. John's wort. Photochemistry and Photobiology 83, 706-713Google Scholar

182Wong, W.T. et al. (2010) Treatment of geographic atrophy by the topical administration of OT-551: results of a phase II clinical trial. Investigative Ophthalmology Visual Science 2010 Jun 23 [Epub ahead of print]Google Scholar

183Wan, F. and Lenardo, M.J. (2010) The nuclear signaling of NF-kappaB: current knowledge, new insights, and future perspectives. Cell Research 20, 24-33Google Scholar

184Dutta, J. et al. (2006) Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene 25, 6800-6816Google Scholar

185Hatada, E.N., Krappmann, D. and Scheidereit, C. (2000) NF-kappaB and the innate immune response. Current Opinion in Immunology 12, 52-58Google Scholar

186Mankan, A.K. et al. (2009) NF-kappaB regulation: the nuclear response. Journal of Cellular and Molecular Medicine 13, 631-643Google Scholar

187Nordberg, J. and Arner, E.S. (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radical Biology and Medicine 31, 1287-1312Google Scholar

188Berndt, C., Lillig, C.H. and Holmgren, A. (2007) Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. AJP – Heart and Circulatory Physiology 292, H1227-H1236Google Scholar

189Wang, X.W. et al. (2008) Thioredoxin-like 6 protects retinal cell line from photooxidative damage by upregulating NF-kappaB activity. Free Radical Biology and Medicine 45, 336-344Google Scholar

190Tanito, M. et al. (2002) Cytoprotective effect of thioredoxin against retinal photic injury in mice. Investigative Ophthalmology and Visual Science 43, 1162-1167Google Scholar

191Arnér, E.S.J. and Holmgren, A. (2006) The thioredoxin system in cancer. Seminars in Cancer Biology 16, 420-426Google Scholar

192Migliaccio, E. et al. (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313Google Scholar

193Wu, Z. et al. (2006) Reduction of p66Shc suppresses oxidative damage in retinal pigmented epithelial cells and retina. Journal of Cellular Physiology 209, 996-1005Google Scholar

194Capitani, N. et al. (2010) Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia. Blood 115, 3726-3736Google Scholar

195Li, Q. et al. (2008) Downregulation of p22phox in retinal pigment epithelial cells inhibits choroidal neovascularization in mice. Molecular Therapy: The Journal of the American Society of Gene Therapy 16, 1688-1694Google Scholar

196Chen, B. et al. (2009) Delivery of antioxidant enzyme genes to protect against ischemia/reperfusion-induced injury to retinal microvasculature. Investigative Ophthalmology and Visual Science 50, 5587-5595Google Scholar

197Rex, T.S. et al. (2004) Adenovirus-mediated delivery of catalase to retinal pigment epithelial cells protects neighboring photoreceptors from photo-oxidative stress. Human Gene Therapy 15, 960-967Google Scholar

198Gao, X. and Talalay, P. (2004) Induction of phase 2 genes by sulforaphane protects retinal pigment epithelial cells against photooxidative damage. Proceedings of the National Academy of Sciences of the United States of America 101, 10446-10451Google Scholar

199del, V.C. et al. (2008) Demonstration by redox fluorometry that sulforaphane protects retinal pigment epithelial cells against oxidative stress. Investigative Ophthalmology and Visual Science 49, 2606-2612Google Scholar

200Liu, X.P. et al. (2007) Extract of Ginkgo biloba induces phase 2 genes through Keap1-Nrf2-ARE signaling pathway. Life Sciences 80, 1586-1591Google Scholar

201Talalay, P. (2000) Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors 12, 5-11Google Scholar

202Talalay, P., Dinkova-Kostova, A.T. and Holtzclaw, W.D. (2003) Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Advances in Enzyme Regulation 43, 121-134Google Scholar

203Dong, A. et al. (2007) Increased expression of glial cell line-derived neurotrophic factor protects against oxidative damage-induced retinal degeneration. Journal of Neurochemistry 103, 1041-1052Google Scholar

204Godley, B.F. et al. (2002) Bcl-2 overexpression increases survival in human retinal pigment epithelial cells exposed to H(2)O(2). Experimental Eye Research 74, 663-669CrossRef Google Scholar

205Chen, J. et al. (2006) Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides. Nature Nanotechnology 1, 142-150Google Scholar

206Fawcett, R.J. and Osborne, N.N. (2007) Flupirtine attenuates sodium nitroprusside-induced damage to retinal photoreceptors, in situ. Brain Research Bulletin 73, 278-288Google Scholar

207Pitha-Rowe, I. et al. (2009) Synthetic triterpenoids attenuate cytotoxic retinal injury: cross-talk between Nrf2 and PI3 K/AKT signaling through inhibition of the lipid phosphatase PTEN. Investigative Ophthalmology and Visual Science 50, 5339-5347Google Scholar

208Petronelli, A., Pannitteri, G. and Testa, U. (2009) Triterpenoids as new promising anticancer drugs. Anticancer Drugs 20, 880-892Google Scholar

209Onaivi, E.S. (2009) Cannabinoid receptors in brain: pharmacogenetics, neuropharmacology, neurotoxicology, and potential therapeutic applications. International Review of Neurobiology 88, 335-369Google Scholar

210Matias, I. et al. (2006) Changes in endocannabinoid and palmitoylethanolamide levels in eye tissues of patients with diabetic retinopathy and age-related macular degeneration. Prostaglandins, Leukotrienes, and Essential Fatty Acids 75, 413-418Google Scholar

211Wei, Y., Wang, X. and Wang, L. (2009) Presence and regulation of cannabinoid receptors in human retinal pigment epithelial cells. Molecular Vision 15, 1243-1251Google Scholar

212Butler, H. and Korbonits, M. (2009) Cannabinoids for clinicians: the rise and fall of the cannabinoid antagonists. European Journal of Endocrinology 161, 655-662Google Scholar

213Lacombe, C. and Mayeux, P. (1998) Biology of erythropoietin. Haematologica 83, 724-732Google Scholar

214Katavetin, P. et al. (2007) Antioxidative effects of erythropoietin. Kidney International. Supplement S10-S15Google Scholar

215Chung, H. et al. (2009) Neuroprotective role of erythropoietin by antiapoptosis in the retina. Journal of Neuroscience Research 87, 2365-2374Google Scholar

216Shah, S.S., Tsang, S.H. and Mahajan, V.B. (2009) Erythropoetin receptor expression in the human diabetic retina. BMC Research Notes 2, 234Google Scholar

217Wang, Z.Y. et al. (2009) Erythropoietin protects retinal pigment epithelial cells from oxidative damage. Free Radical Biology and Medicine 46, 1032-1041Google Scholar

218Rex, T.S. et al. (2009) Neuroprotection of photoreceptors by direct delivery of erythropoietin to the retina of the retinal degeneration slow mouse. Experimental Eye Research 89, 735-740Google Scholar

219Yodoi, Y. et al. (2007) Circulating hematopoietic stem cells in patients with neovascular age-related macular degeneration. Investigative Ophthalmology and Visual Science 48, 5464-5472Google Scholar

220Mattison, J.A. et al. (2007) Dietary restriction in aging nonhuman primates. Interdiscip Top Gerontol 35, 137-158Google Scholar

221Li, D., Sun, F. and Wang, K. (2003) Caloric restriction retards age-related changes in rat retina. Biochemical and Biophysical Research Communications 309, 457-463Google Scholar

222Gouras, P. et al. (2008) Drusenoid maculopathy in rhesus monkeys (Macaca mulatta): effects of age and gender. Graefes Archive for Clinical and Experimental Ophthalmology 246, 1395-1402Google Scholar

223Kanda, A., Chen, W., Othman, M. et al. (2007) A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 104, 16227-16232Google Scholar

Article contents

Oxidation and age-related macular degeneration: insights from molecular biology

Abstract

Access options

References

References

Further reading, resources and contacts

This article has been cited by the following publications. This list is generated based on data provided by Crossref.

Article contents

Oxidation and age-related macular degeneration: insights from molecular biology

Abstract

Access options

References

References

Further reading, resources and contacts

Save article to Kindle

Save article to Dropbox

Save article to Google Drive

Reply to: Submit a response

Your details

You have entered the maximum number of contributors

Conflicting interests