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Jie Fan, Masahiro Kono; Cone Opsin Inverse Agonists Promote Light-independent Cone Survival in Chromophore-deficient Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5454.
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To determine the efficacy of cyclocitral and ß -ionone as light-insensitive ligands that preserve cones in Rpe65-/-Rho-/- mice. Cones degenerate rapidly in chromophore-deficient mouse models for Leber Congenital Amaurosis. This degeneration can be slowed by exogenous supplementation of 11-cis retinal in the dark, but as we have recently shown, not under normal cyclic light conditions. We have also found cyclocitral to be an inverse agonist for both short and long wavelength-sensitive cone opsins; whereas, and ß -ionone is an inverse agonist for only the long wavelength-sensitive cone opsin.
Cyclocitral or ß -ionone was introduced to Rpe65-/-Rho-/- mice at P10 as a single subcutaneous injection mixed with Matrigel. Mice were maintained under cyclic light conditions. Cone morphology was assessed by fluorescence microscopy. Cross sections were used to visualize cone opsin localization, and flat-mounted retinas used to determine the number of cone opsin-containing cells.
The cyclocitral treated mice show an increase in proper localization of both short and long wavelength-sensitive cone opsins and an increase in cone cell numbers containing both types of opsins relative to cones in untreated mice. On the other hand, ß -ionone showed improvement in opsin localization and cone cell numbers with primarily the long wavelength-sensitive cones, not the short wavelength-sensitive cones.
Inverse agonists to cone opsins may be an important feature for the development and survival of cones, and a new light-independent treatment strategy for preserving cones in chromophore-deficient diseases.
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