Primary amines protect against retinal degeneration in mouse models of retinopathies
Open accessAbstract
Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore 11-cis-retinal and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomerized product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine-containing Food and Drug Administration (FDA)-approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by MS. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal-induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that shows features of Stargardt's disease and age-related retinal degeneration.
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Retinylamine and other primary amines buffer the toxic effect of all-trans-retinal by inhibiting the visual cycle or by chemically trapping excess all-trans-retinal as a Schiff base when it cannot be cleared by reduction to all-trans-retinol.
“Retinylamine and other primary amines were employed to buffer the toxic effect of all-trans-retinal either by inhibiting the visual cycle or by chemically trapping an excess of all-trans-retinal in the form of a Schiff base when it could not be effectively cleared from photoreceptor cells by reduction to all-trans-retinol (Figure 36).318,572,573”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [572]
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“On the other hand, a detoxifying role for A2E itself has also been suggested as it removes the highly toxic free all-trans retinal (Maeda et al., 2011, 2009a; Roberts et al., 2002).”
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Self-citation
- Authors
- Maeda, A., Golczak, M., Chen, Y., Okano, K., Kohno, H., Shiose, S., Ishikawa, K., Harte, W., Palczewska, G., Maeda, T., & Palczewski, K.
- Affiliations
- Case Western Reserve University (US)
- Polgenix (United States) (US)
- Corresponding author
- Palczewski, Krzysztof
- Venue
- Nature Chemical Biology
- Published
- 2011-12-25
- Volume
- 8
- Issue
- 2
- Pages
- 170-178
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3518042
- OpenAlex
- W2004577874
- Cited by
- 135
- References
- 51
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 3 · 2021: 12 · 2020: 12 · 2019: 5 · 2018: 13 · 2017: 8 · 2016: 12 · 2015: 13 · 2014: 16 · 2013: 14 · 2012: 8
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (EY021126, K08EY019880, EY019880, EY009339, K08EY019031, R24EY021126, EY019031, P30 EY-11373, P30EY011373, R01EY009339)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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
- primary amines, retinal degeneration, Stargardt disease, age-related retinal degeneration, all-trans-retinal, Schiff base adducts, retinoid cycle, 11-cis-retinal regeneration, lipofuscin, FDA-approved drugs, drug repurposing
- MeSH terms
- Amines, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Macular Degeneration, Retinal Degeneration, Retinaldehyde, Schiff Bases, United States, United States Food and Drug Administration, Mice
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