Cited by 97Retinal Diseases and TreatmentsRetinal Development and DisordersRetinoids in leukemia and cellular processes

A1120, a Nonretinoid RBP4 Antagonist, Inhibits Formation of Cytotoxic Bisretinoids in the Animal Model of Enhanced Retinal Lipofuscinogenesis

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Dobri, Nicoleta, Qin, Qiong, Kong, Jian, Yamamoto, Kazunori, Liu, Zhao, Moiseyev, Gennadiy, Ma, Jian-xing, Allikmets, Rando +2 more·2013·Investigative Opthalmology & Visual Science

Abstract

PURPOSE: Excessive accumulation of lipofuscin is associated with pathogenesis of atrophic age-related macular degeneration (AMD) and Stargardt disease. Pharmacologic inhibition of the retinol-induced interaction of retinol-binding protein 4 (RBP4) with transthyretin (TTR) in the serum may decrease the uptake of serum retinol to the retina and reduce formation of lipofuscin bisretinoids. We evaluated in vitro and in vivo properties of the new nonretinoid RBP4 antagonist, A1120. METHODS: RBP4 binding potency, ability to antagonize RBP4-TTR interaction, and compound specificity were analyzed for A1120 and for the prototypic RBP4 antagonist fenretinide. A1120 ability to inhibit RPE65-mediated isomerohydrolase activity was assessed in the RPE microsomes. The in vivo effect of A1120 administration on serum RBP4, visual cycle retinoids, lipofuscin bisretinoids, and retinal visual function was evaluated using a combination of biochemical and electrophysiologic techniques. RESULTS: In comparison to fenretinide, A1120 did not act as a RARα agonist, while exhibiting superior in vitro potency in RBP4 binding and RBP4-TTR interaction assays. A1120 did not inhibit isomerohydrolase activity in the RPE microsomes. A1120 dosing in mice induced 75% reduction in serum RBP4, which correlated with reduction in visual cycle retinoids and ocular levels of lipofuscin fluorophores. A1120 dosing did not induce changes in kinetics of dark adaptation. CONCLUSIONS: A1120 significantly reduces accumulation of lipofuscin bisretinoids in the Abca4(-/-) animal model. This activity correlates with reduction in serum RBP4 and visual cycle retinoids confirming the mechanism of action for A1120. In contrast to fenretinide, A1120 does not act as a RARα agonist indicating a more favorable safety profile for this nonretinoid compound.

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Crossref · 10.1167/iovs.12-10050

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  • Inhibiting RPE65 or RBP4 slows the visual cycle, deprives photoreceptors of 11-cis-retinal, and consequently reduces accumulation of toxic A2E.

    “An example is slowing the visual cycle by inhibiting RPE65 or RBP4, which deprives photoreceptors of 11-cis-retinal and consequently reduces the accumulation of toxic A2E.”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [103]

  • Inhibiting RPE65 or RBP4 causes reversible night blindness as a side effect.

    “As a side effect, reversible night blindness occurs [101,102,103,104].”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [103]

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Authors
Dobri, N., Qin, Q., Kong, J., Yamamoto, K., Liu, Z., Moiseyev, G., Ma, J.-X., Allikmets, R., Sparrow, J. R., & Petrukhin, K.
Affiliations
  • From the Departments of Ophthalmology and
  • Medicine Endocrinology and
  • University of Oklahoma Health Sciences Center (US)
  • Columbia University (US)
Corresponding author
  • Dobri, Nicoleta
  • Qin, Qiong
  • Kong, Jian
  • Yamamoto, Kazunori
  • Liu, Zhao
  • Moiseyev, Gennadiy
  • Ma, Jian-xing
  • Allikmets, Rando
  • Sparrow, Janet R.
  • Petrukhin, Konstantin
Venue
Investigative Opthalmology & Visual Science
Published
2013-01-07
Volume
54
Issue
1
Pages
85
ISSN
  • 0146-0404 (ISSN-L)
  • 1552-5783
OpenAlex
W2073655465
Cited by
91
References
54
Citations by year
2026: 4 · 2025: 9 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 11 · 2020: 13 · 2019: 4 · 2018: 7 · 2017: 4 · 2016: 7 · 2015: 4 · 2014: 6 · 2013: 4
FWCI
4.49
Type
journal article
Language
en
Open access
Locations
  • Investigative Ophthalmology & Visual Science (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Research to Prevent Blindness (P30EY019007, EY019861)
  • National Institutes of Health (EY019861, EY019007)
  • National Eye Institute (R01EY012951, P30EY019007, R24EY019861, R01EY021163)
  • National Institute of General Medical Sciences (P20GM104934)
  • National Institute of Neurological Disorders and Stroke (R21NS067594, U01NS074476)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords
retinol-binding protein 4, prealbumin, lipofuscin, bisretinoids, age-related macular degeneration, Stargardt disease, fenretinide, dark adaptation
MeSH terms
Animals, Antineoplastic Agents, Cattle, Disease Models, Animal, Humans, Hydrolases, Ligands, Lipofuscin, Macular Degeneration, Mice, Inbred C57BL, Mice, Mutant Strains, Piperidines, Prealbumin, Retinoids, Fenretinide, ATP-Binding Cassette Transporters, Mice, Retinol-Binding Proteins, Plasma, Mice, 129 Strain

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