Received for publication May 19, 2006.
Revised July 12, 2006.
Accepted for publication July 12, 2006.

Effects of potent inhibitors of the retinoid cycle on visual function and photoreceptor protection from light damage in mice

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 which 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 due to its storage in a pro-drug 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.

Key words: Protein-binding, Regulation - physiological, Structure/function/mechanism, Toxicant-induced gene express

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