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

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

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

Akiko Maeda,Tadao Maeda,Marcin Golczak,Yoshikazu Imanishi,Patrick Leahy,Ryo Kubota,Krzysztof Palczewski,

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.

Effects of potent inhibitors of the retinoid cycle on visual function and photoreceptor protection from light damage in mice. Publishing Authors By Initials

A Maeda,T Maeda,M Golczak,Y Imanishi,P Leahy,R Kubota,K Palczewski,

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

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular pharmacology

VOLUME: 70

Page Numbers: 1220-9

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ISSN: 0026-895X

DAY: 12

MONTH: 07

YEAR: 2006

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

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LANGUAGE: eng

NlmUniqueID: 35623

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Grant and Affiliation Information for Effects of potent inhibitors of the retinoid cycle on visual function and photoreceptor protection from light damage in mice.

AFFILIATION: Department of Pharmacology, and Comprehensive Cancer Center, Case School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, BRB R924, Cleveland, OH 44106-4965, USA.

Country: United States

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MEDLINETA: Mol Pharmacol

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