Journal
NATURE CHEMICAL BIOLOGY
Volume 8, Issue 2, Pages 170-178Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.759
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Funding
- US National Institutes of Health [EY009339, EY021126, EY019031, EY019880, P30 EY11373]
- State of Ohio Department of Development [TECH 09-004]
- Third Frontier Commission
- Research to Prevent Blindness
- Ohio Lion Eye Research Foundation
- Foundation Fighting Blindness
- Fight for Sight
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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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