Abstract |
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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Authors | Akiko Maeda, Marcin Golczak, Yu Chen, Kiichiro Okano, Hideo Kohno, Satomi Shiose, Kaede Ishikawa, William Harte, Grazyna Palczewska, Tadao Maeda, Krzysztof Palczewski |
Journal | Nature chemical biology
(Nat Chem Biol)
Vol. 8
Issue 2
Pg. 170-8
(Dec 25 2011)
ISSN: 1552-4469 [Electronic] United States |
PMID | 22198730
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amines
- Schiff Bases
- Retinaldehyde
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Topics |
- Amines
(pharmacology, therapeutic use)
- Animals
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Macular Degeneration
(drug therapy)
- Mice
- Retinal Degeneration
(drug therapy, prevention & control)
- Retinaldehyde
(therapeutic use)
- Schiff Bases
(analysis)
- United States
- United States Food and Drug Administration
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