Mitotropic Compounds for the Treatment of Age-Related Macular Degeneration

Recent histopathologic studies have shown that mitochondria and peroxisomes of the retinal pigment epithelium may play a central role in the pathophysiology of age-related macular degeneration (AMD). We supposed that compounds which improve mitochondrial functions (mitotropic compounds) may show beneficial effects in preventing AMD. Fourteen patients affected by early AMD were treated with a mixture containing acetyl-L-carnitine (ALC), polyunsaturated fatty acids (PUFAs), coenzyme Q10 (CoQ10) and vitamin E, while an equal number of age- and sex-matched patients affected by early AMD were treated with vitamin E only. Recovery time after macular photostress, foveal sensitivity and mean defect in the visual field as well as blood lipid levels were recorded at the beginning and after 3, 6, 9, 12 and 24 months of follow-up. In the treated group, all the visual functions showed slight improvement which was evident after 3 months of treatment and remained nearly stationary by the end of 24 months. The same tests in the control group showed slow worsening. The divergence between treated and control groups became more marked with time, but the difference was not significant at any time of the follow-up. These findings suggest that the blend of ALC, PUFA, CoQ10 and vitamin E may improve retinal functions in early AMD.

[1]  D. Das,et al.  Dual involvement of coenzyme Q10 in redox signaling and inhibition of death signaling in the rat heart mitochondria. , 2001, Antioxidants & redox signaling.

[2]  R. E. Anderson,et al.  Evidence for rod outer segment lipid peroxidation following constant illumination of the rat retina. , 1983, Investigative ophthalmology & visual science.

[3]  M. T. Clandinin,et al.  Dietary 20:4n-6 and 22:6n-3 Modulates the Profile of Long- and Very-Long-Chain Fatty Acids, Rhodopsin Content, and Kinetics in Developing Photoreceptor Cells , 2000, Pediatric Research.

[4]  J D Gottsch,et al.  Oxidative damage and age-related macular degeneration. , 1999, Molecular vision.

[5]  R. Browne,et al.  Characterization of peroxidized lipids in Bruch's membrane. , 1999, Retina.

[6]  H. Sprecher,et al.  Polyunsaturated fatty acid biosynthesis: a microsomal-peroxisomal process. , 1999, Prostaglandins, leukotrienes, and essential fatty acids.

[7]  R. Klein,et al.  Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. , 1998, American journal of epidemiology.

[8]  C. Hoppel,et al.  Fatty acid import into mitochondria. , 2000, Biochimica et biophysica acta.

[9]  G. Carella,et al.  Does Coenzyme Q10 Play a Role in Opposing Oxidative Stress in Patients with Age-Related Macular Degeneration? , 2000, Ophthalmologica.

[10]  J. Joseph,et al.  Essential fatty acids and the brain: possible health implications , 2000, International Journal of Developmental Neuroscience.

[11]  A Hofman,et al.  Risk factors for age-related macular degeneration: Pooled findings from three continents. , 2001, Ophthalmology.

[12]  B. Jeffrey,et al.  n-3 fatty acid deficiency alters recovery of the rod photoresponse in rhesus monkeys. , 2002, Investigative ophthalmology & visual science.

[13]  T. Yoshikawa,et al.  Paraoxonase gene polymorphisms and plasma oxidized low-density lipoprotein level as possible risk factors for exudative age-related macular degeneration. , 2001, American journal of ophthalmology.

[14]  P. Mitchell,et al.  Serum beta carotene, alpha tocopherol, and age-related maculopathy: the Blue Mountains Eye Study. , 1997, American journal of ophthalmology.

[15]  D. Liebler,et al.  The Reduction of α-Tocopherolquinone by Human NAD(P)H:Quinone Oxidoreductase: The Role of α-Tocopherolhydroquinone as a Cellular Antioxidant , 1997 .

[16]  T. Freddo,et al.  The lipid composition of drusen, Bruch's membrane, and sclera by hot stage polarizing light microscopy. , 2001, Investigative ophthalmology & visual science.

[17]  W. M. Kozak,et al.  Acetyl-L-Carnitine Corrects Electroretinographic Deficits in Experimental Diabetes , 1993, Diabetes.

[18]  A. Vingrys,et al.  Effects of dietary n-3 fatty acid deficiency and repletion in the guinea pig retina. , 1999, Investigative ophthalmology & visual science.

[19]  L Frøyland,et al.  Mitochondrion is the principal target for nutritional and pharmacological control of triglyceride metabolism. , 1997, Journal of lipid research.

[20]  C. Chow,et al.  Dietary coenzyme Q10 and vitamin E alter the status of these compounds in rat tissues and mitochondria. , 2000, The Journal of nutrition.

[21]  M. Sandberg,et al.  SLOW PHOTOSTRESS RECOVERY AND DISEASE SEVERITY IN AGE‐RELATED MACULAR DEGENERATION , 1995, Retina.

[22]  A Hofman,et al.  Age-specific prevalence and causes of blindness and visual impairment in an older population: the Rotterdam Study. , 1998, Archives of ophthalmology.

[23]  J. Weiter,et al.  The macular photostress test in diabetic retinopathy and age-related macular degeneration. , 1990, Archives of ophthalmology.

[24]  R. Stocker,et al.  Alpha-tocopheryl hydroquinone is an efficient multifunctional inhibitor of radical-initiated oxidation of low density lipoprotein lipids. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Belda Sanchis,et al.  [Are blood lipids a risk factor for age-related macular degeneration?]. , 2001, Archivos de la Sociedad Española de Oftalmología.

[26]  V. Porciatti,et al.  Spatial-frequency-dependent changes in the human pattern electroretinogram after acute acetyl-l-carnitine administration , 1991, Graefe's Archive for Clinical and Experimental Ophthalmology.

[27]  E. Rimm,et al.  Prospective study of dietary fat and the risk of age-related macular degeneration. , 2001, The American journal of clinical nutrition.

[28]  R Hiller,et al.  Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. , 1994, JAMA.

[29]  R. Klein,et al.  Dietary fat and age-related maculopathy. , 1995, Archives of ophthalmology.

[30]  D. Kyle,et al.  The effect of dietary docosahexaenoic acid on plasma lipoproteins and tissue fatty acid composition in humans , 1997, Lipids.

[31]  T. Sanders,et al.  Essential fatty acids, plasma cholesterol, and fat-soluble vitamins in subjects with age-related maculopathy and matched control subjects. , 1993, The American journal of clinical nutrition.

[32]  P. Mitchell,et al.  Dietary antioxidants and age-related maculopathy: the Blue Mountains Eye Study. , 1999, Ophthalmology.

[33]  G. Vatassery Determination of tocopherols and tocopherolquinone in human red blood cell and platelet samples. , 1994, Methods in enzymology.

[34]  W. Gordon,et al.  Preferential uptake and metabolism of docosahexaenoic acid in membrane phospholipids from rod and cone photoreceptor cells of human and monkey retinas , 1990, Journal of neuroscience research.

[35]  C. Remé,et al.  Effect of dietary fish oil on acute light-induced photoreceptor damage in the rat retina. , 1994, Investigative ophthalmology & visual science.

[36]  E. Birch,et al.  Impact of Early Dietary Intake and Blood Lipid Composition of Long-Chain Polyunsaturated Fatty Acids on Later Visual Development , 2000, Journal of pediatric gastroenterology and nutrition.

[37]  W. Willett,et al.  Dietary fat and risk for advanced age-related macular degeneration. , 2001, Archives of ophthalmology.

[38]  R. Klein,et al.  Relationship of dietary fat to age-related maculopathy in the Third National Health and Nutrition Examination Survey. , 2001, Archives of ophthalmology.

[39]  J. Quiles,et al.  Coenzyme Q content depends upon oxidative stress and dietary fat unsaturation. , 1997, Molecular aspects of medicine.

[40]  A. Leaf,et al.  Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[41]  R. Uauy,et al.  Essential fat requirements of preterm infants. , 2000, The American journal of clinical nutrition.

[42]  S. Ferdinandusse,et al.  Identification of the peroxisomal beta-oxidation enzymes involved in the biosynthesis of docosahexaenoic acid. , 2001, Journal of lipid research.

[43]  Jennifer I. Lim,et al.  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. , 2001, Archives of ophthalmology.

[44]  R. S. Sohal,et al.  Effects of coenzyme Q10 and alpha-tocopherol administration on their tissue levels in the mouse: elevation of mitochondrial alpha-tocopherol by coenzyme Q10. , 1999, Free radical biology & medicine.

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

[46]  R. Uauy,et al.  Essential fatty acids in early life: structural and functional role , 2000, Proceedings of the Nutrition Society.

[47]  S. Ando,et al.  Enhancement of learning capacity and cholinergic synaptic function by carnitine in aging rats , 2001, Journal of neuroscience research.

[48]  Ian J Constable,et al.  Lipofuscin of the retinal pigment epithelium: A review , 1995, Eye.

[49]  R. S. Sohal,et al.  Effects of coenzyme Q10 and α-tocopherol administration on their tissue levels in the mouse: elevation of mitochondrial α-tocopherol by coenzyme Q10 , 1999 .

[50]  N. Ilhan,et al.  L-Carnitine in Experimental Retinal Ischemia-Reperfusion Injury , 2002, Ophthalmologica.

[51]  E. Birch,et al.  A randomized controlled trial of early dietary supply of long‐chain polyunsaturated fatty acids and mental development in term infants , 2000, Developmental medicine and child neurology.

[52]  N. Bazan,et al.  Post-Golgi Vesicles Cotransport Docosahexaenoyl-Phospholipids and Rhodopsin during Frog Photoreceptor Membrane Biogenesis* , 1997, The Journal of Biological Chemistry.

[53]  S. Browne,et al.  Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[54]  E. Birch,et al.  Essential fatty acids in visual and brain development , 2001, Lipids.