The DOI matches its Crossref record; 42 of the 43 references it cites were found in a registry or an index.
Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration
Open accessAbstract
Recessive Stargardt's macular degeneration is an inherited blinding disease of children caused by mutations in the ABCR gene. The primary pathologic defect in Stargardt's disease is accumulation of toxic lipofuscin pigments such as N -retinylidene- N -retinylethanolamine (A2E) in cells of the retinal pigment epithelium. This accumulation appears to be responsible for the photoreceptor death and severe visual loss in Stargardt's patients. Here, we tested a therapeutic strategy to inhibit lipofuscin accumulation in a mouse model of recessive Stargardt's disease. Isotretinoin (Accutane) has been shown to slow the synthesis of 11- cis -retinaldehyde and regeneration of rhodopsin by inhibiting 11- cis -retinol dehydrogenase in the visual cycle. Light activation of rhodopsin results in its release of all-trans -retinaldehyde, which constitutes the first reactant in A2E biosynthesis. Accordingly, we tested the effects of isotretinoin on lipofuscin accumulation in abcr −/− knockout mice. Isotretinoin blocked the formation of A2E biochemically and the accumulation of lipofuscin pigments by electron microscopy. We observed no significant visual loss in treated abcr −/− mice by electroretinography. Isotretinoin also blocked the slower, age-dependent accumulation of lipofuscin in wild-type mice. These results corroborate the proposed mechanism of A2E biogenesis. Further, they suggest that treatment with isotretinoin may inhibit lipofuscin accumulation and thus delay the onset of visual loss in Stargardt's patients. Finally, the results suggest that isotretinoin may be an effective treatment for other forms of retinal or macular degeneration associated with lipofuscin accumulation.
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“This impairs chromophore, 11-cis-retinal, and slows rhodopsin (RHO) regeneration which can cause night blindness.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [18]
In the citing paper
“However, on the other hand, it reduces the accumulation of toxic byproducts of the visual cycle, such as N-retinyl-N-retinylidene ethanolamine (A2E) [16,17,18].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [18]
In the citing paper
“In retina in the retinal pigment epithelium (RPE), isotretinoin inhibits two key visual cycle enzymes, RPE-specific 65 kDa protein (RPE65) [16] and 11-cis-retinol dehydrogenase [17,18] (Figure 1).”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [18]
Citations
Cites
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351
Prevalence of age-related maculopathy
Klein, R., Klein, B. E. K., & Linton, K. L. P. (1992) · Ophthalmology · doi:10.1016/s0161-6420(92)31871-8 · Cited by 1,845
Leibowitz, H. M., Krueger, D. E., Maunder, L. R., Milton, R. C., KINI, M. M., Kahn, H. A., Nickerson, R. J., Pool, J., Colton, T., Ganley, J. P., et al. (1980) · PubMed · Cited by 1,250
Weng, J., Mata, N. L., Azarian, S. M., Tzekov, R. T., Birch, D. G., & Travis, G. H. (1999) · Cell · doi:10.1016/s0092-8674(00)80602-9 · Cited by 881
Self-citationMutation of the Stargardt Disease Gene ( ABCR ) in Age-Related Macular Degeneration
Allikmets, R. L., Shroyer, N. F., Singh, N., Seddon, J. M., Lewis, R. A., Bernstein, P. S., Peiffer, A. P., Zabriskie, N. A., Li, Y., Hutchinson, A. A., et al. (1997) · Science · doi:10.1126/science.277.5333.1805 · Cited by 879
Prolonged Remissions of Cystic and Conglobate Acne with 13-cis-Retinoic Acid
Peck, G. L., Olsen, T. G., Yoder, F. W., Strauss, J. S., Downing, D. T., Pandya, M. D., Butkus, D., & ARNAUD‐BATTANDIER, J. (1979) · New England Journal of Medicine · doi:10.1056/nejm197902153000701 · Cited by 519
Parish, C. A., Hashimoto, M., Nakanishi, K., Dillon, J., & Sparrow, J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14609 · Cited by 474
Mata, N. L., Weng, J., & Travis, G. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130110497 · Cited by 456
Self-citationIsomerization and Oxidation of Vitamin A in Cone-Dominant Retinas
Mata, N. L., Radu, R. A., Clemmons, R. S., & Travis, G. H. (2002) · Neuron · doi:10.1016/s0896-6273(02)00912-1 · Cited by 382
Self-citationSun, H., Molday, R. S., & Nathans, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.8269 · Cited by 353
Age-related Macular Degeneration
Suter, M., Remé, C., Grimm, C., Wenzel, A., Jäättelä, M., Esser, P., Kociok, N., Leist, M., & Richter, C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m007049200 · Cited by 315
The 220-kDa Rim Protein of Retinal Rod Outer Segments Is a Member of the ABC Transporter Superfamily
Illing, M., Molday, L. L., & Molday, R. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.15.10303 · Cited by 304
Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin.
Schütt, F., Davies, S., Kopitz, J., Holz, F. G., & Boulton, M. (2000) · PubMed · Cited by 292
Retinal Pigment Epithelial Abnormalities in Fundus Flavimmaculatus
Eagle, R. C., Lucier, A. C., Bernardino, V. B., & Yanoff, M. (1980) · Ophthalmology · doi:10.1016/s0161-6420(80)35106-3 · Cited by 287
Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE.
Sparrow, J. R., Zhou, J., Ben‐Shabat, S., Vollmer-Snarr, H. R., Itagaki, Y., & Nakanishi, K. (2002) · PubMed · Cited by 284
Finnemann, S. C., Leung, L. W., & Rodriguez-Boulan, E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052025899 · Cited by 283
Kupper, C. (1980) · Survey of Ophthalmology · doi:10.1016/0039-6257(80)90015-6 · Cited by 246
Interactions between the retinal pigment epithelium and the neural retina
Steinberg, R. H. (1985) · Documenta Ophthalmologica · doi:10.1007/bf00158922 · Cited by 234
Mata, N. L., Tzekov, R. T., Liu, X., Weng, J., Birch, D. G., & Travis, G. H. (2001) · PubMed · Cited by 219
Self-citationHistopathology and immunocytochemistry of the neurosensory retina in fundus flavimaculatus.
Birnbach, C., Järveläínen, M., Possin, D., & Milam, A. (1994) · Ophthalmology (Rochester, Minn.) · doi:10.1016/s0161-6420(13)31725-4 · Cited by 212
Ocular Age Pigment “A2-E”: An Unprecedented Pyridinium Bisretinoid
Sakai, N., Decatur, J. D., Nakanishi, K., & Eldred, G. E. (1996) · Journal of the American Chemical Society · doi:10.1021/ja953480g · Cited by 203
Systematic Evaluation of the Mouse Eye
(2001) · CRC Press eBooks · doi:10.1201/9781420041606 · Cited by 198
Ocular side effects possibly associated with isotretinoin usage
Fraunfelder, F. T., Fraunfelder, F. W., & Edwards, R. (2001) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(01)01024-8 · Cited by 177
The A-wave of the human electroretinogram and rod receptor function.
Hood, D. C., & Birch, D. G. (1990) · PubMed · Cited by 172
Azarian, S. M., & Travis, G. H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00517-6 · Cited by 170
Self-citationPalczewski, K., Hooser, J. P. V., Garwin, G. G., Chen, J., Liou, G. I., & Saari, J. C. (1999) · Biochemistry · doi:10.1021/bi990504d · Cited by 157
Sieving, P. A., Chaudhry, P. S., Kondo, M., Provenzano, M. J., Wu, D. M., Carlson, T. J., Bush, R. A., & Thompson, D. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1835 · Cited by 151
Self-citationFong, S. –., Liou, G. I., Landers, R. A., Alvarez, R., & Bridges, C. D. B. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)82174-7 · Cited by 149
Hood, D. C., & Birch, D. G. (1993) · Vision Research · doi:10.1016/0042-6989(93)90027-t · Cited by 148
Driessen, C. A. G. G., Winkens, H. J., Hoffmann, K., Kuhlmann, L. D., Janssen, B. P. M., Van Vugt, A. H. M., Van Hooser, J. P., Wieringa, B. E., Deutman, A. F., Palczewski, K., et al. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.12.4275-4287.2000 · Cited by 132
Ahn, J., Wong, J. T., & Molday, R. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000555200 · Cited by 130
Teratogenicity of isotretinoin revisited: Species variation and the role of all-trans-retinoic acid
Nau, H. (2001) · Journal of the American Academy of Dermatology · doi:10.1067/mjd.2001.113720 · Cited by 119
Guyer, D. R., Yannuzzi, L. A., Chang, S., Shields, J. A., Green, R. W., & Wilkinson, C. P. (1999) · Retina · doi:10.1097/00006982-199903000-00024 · Cited by 112
Abnormal Retinal Function Associated With Isotretinoin Therapy for Acne
Weleber, R. G., Denman, S. T., Hanifin, J. M., & Cunningham, W. J. (1986) · Archives of Ophthalmology · doi:10.1001/archopht.1986.01050180065031 · Cited by 92
Photochemistry and stereoselectivity of cellular retinaldehyde-binding protein from bovine retina.
Saari, J. C., & Bredberg, D. L. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47610-7 · Cited by 91
McCannel, C. A. (1999) · Mayo Clinic Proceedings · doi:10.4065/74.10.1053-b · Cited by 56
Artificial Induction of Melatonin Rhythms by Programmed Microinfusion
Lynch, H. J., Rivest, R. W., & Wurtman, C. J. (2008) · Neuroendocrinology · doi:10.1159/000123059 · Cited by 52
The molecular basis of retinoic acid induced night blindness
Law, W. C., & Rando, R. R. (1989) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(89)92674-0 · Cited by 48
Suzuki, T., Fujita, Y., Noda, Y., & Miyata, S. (1986) · Vision Research · doi:10.1016/0042-6989(86)90185-9 · Cited by 47
Reinboth, J., Gautschi, K., Munz, K., Eldred, G. E., & Remé, C. E. (1997) · Experimental Eye Research · doi:10.1006/exer.1997.0367 · Cited by 38
Gamble, M. V., Mata, N. L., Tsin, A. T., Mertz, J. R., & Blaner, W. S. (2000) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/s0167-4838(99)00232-0 · Cited by 34
Self-citationDistribution of 11-cis LRAT, 11-cis RD and 11-cis REH in bovine retinal pigment epithelium membranes
Mata, N. L., & Tsin, A. T. C. (1998) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/s0005-2760(98)00078-2 · Cited by 25
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1 of the 43 references couldn’t be matched to a known paper.
Research works printed but not linked: 5
- P A Blacharski Fundus flavimaculutus (Raven, New York, 1988).
- N L Mata, R T Tzekov, X R Liu, J Weng, D G Birch, G H Travis Invest Ophthalmol Visual Sci 42, 1685–1690 (2001).
- F Schutt, S Davies, J Kopitz, F G Holz, M E Boulton Invest Ophthalmol Visual Sci 41, 2203–2208 (2000).
- J R Sparrow, J Zhou, S Ben-Shabat, H Vollmer, Y Itagaki, K Nakanishi Invest Ophthalmol Visual Sci 43, 1222–1227 (2002).
- D C Hood, D G Birch Invest Ophthalmol Visual Sci 31, 2070–2081 (1990).
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EVOLUTION OF THE ATP-BINDING CASSETTE (ABC) TRANSPORTER SUPERFAMILY IN VERTEBRATES
Dean, M. C., & Annilo, T. (2005) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.6.080604.162122 · Cited by 646
Wenzel, A., Grimm, C., Samardzija, M., & Remé, C. E. (2004) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2004.08.002 · Cited by 655
The Retinal Pigment Epithelium in Health and Disease
Sparrrow, J. R., Hicks, D., & Hamel, C. (2010) · Current Molecular Medicine · doi:10.2174/156652410793937813 · Cited by 655
Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents
Travis, G. H., Golczak, M., Moise, A. R., & Palczewski, K. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105225 · Cited by 419
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Metadata
- Authors
- Radu, R. A., Mata, N. L., Nusinowitz, S., Liu, X., Sieving, P. A., & Travis, G. H.
- Affiliations
- National Institutes of Health (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-04
- Volume
- 100
- Issue
- 8
- Pages
- 4742-4747
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC153626
- OpenAlex
- W2127150613
- Cited by
- 227
- References
- 43
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 11 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 8 · 2015: 13 · 2014: 11 · 2013: 8 · 2012: 14
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- isotretinoin, lipofuscin accumulation, A2E, retinal pigment epithelium, visual cycle, rhodopsin regeneration
- MeSH terms
- Animals, Dark Adaptation, Disease Models, Animal, Genes, Recessive, Humans, Lipofuscin, Macular Degeneration, Microscopy, Electron, Models, Biological, Pigment Epithelium of Eye, Pyridinium Compounds, Retinal Pigments, Retinoids, Rod Cell Outer Segment, Isotretinoin, Mice, Knockout, ATP-Binding Cassette Transporters, Mice
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