Abstract
Regeneration of the chromophore 11-cis-retinal is essential for the generation of light-sensitive visual pigments in the vertebrate retina. A deficiency in 11-cis-retinal production leads to congenital blindness in humans; however, a buildup of the photoisomerized chromophore can also be detrimental. Such is the case when the photoisomerized all-trans-retinal is produced but cannot be efficiently cleared from the internal membrane of the outer segment discs. Sustained increase of all-trans-retinal can lead to the formation of toxic condensation products in the eye. Thus, there is a need for potent, selective inhibitors that can regulate the flux of retinoids through the metabolism pathway termed the visual (retinoid) cycle. Here we systematically study the effects of the most potent inhibitor of this cycle, retinylamine (Ret-NH2), on visual function in mice. Prolonged, sustainable, but reversible suppression of the visual function was observed by Ret-NH2 as a result of its storage in a prodrug form, N-retinylamides. Direct comparison of other inhibitors such as fenretinide and 13-cis-retinoic acid showed multiple advantages of Ret-NH2 and its amides, including a higher potency, specificity, and lower transcription activation. Our results also revealed that mice treated with Ret-NH2 were completely resistant to the light-induced retina damage. As an experimental tool, Ret-NH2 allows the replacement of the native chromophore with synthetic analogs in wild-type mice to better understand the function of the chromophore in the activation of rhodopsin and its metabolism through the retinoid cycle.
Footnotes
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This research was supported by National Institutes of Health grant EY09339 and P30-EY11373, and a grant from National Neurovision Research Institute (A.M.). This research was supported by the Gene Expression and Genotyping Facility of the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland (P30-CA43703).
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University of Washington and Acucela Inc. may commercialize some of the technology described in this work. K.P. is a consultant for Acucela Inc.
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ABBREVIATIONS: RPE, retinal pigment epithelium; LRAT, lecithin/retinol acyltransferase; RPE65, an RPE-specific 65 kDa protein; A2E, N-retinylidene-N-retinyl ethanolamine; OS, outer segment; Ret-NH2, retinylamine; HPLC, high-performance liquid chromatography; ERG, electroretinogram(s); PBST, phosphate-buffered saline/Triton X-100.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received May 18, 2006.
- Accepted July 12, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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