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Akiko Maeda, Marcin Golczak, Yu Chen, Hideo Kohno, Grazyna Palczewska, Tadao Maeda, Krzysztof Palczewski; Primary Amines Protect The Retina From Degeneration In Mouse Models: Implications For Stargardt’S Disease And Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2213.
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All-trans-retinal (atRAL) is a photo-bleached visual chromophore, that constitutes one of the major intermediates in the visual cycle. Delayed clearance of atRAL from the retina in mice mimics human retinal disorders, indicating a pivotal role for this molecule in the pathogenesis of blinding diseases. We tested the hypothesis that transient sequestration of atRAL by amine drugs, which produce Schiff base adducts, can ameliorate retinal degenerative changes in mice.
Primary amine-containing FDA-approved drugs were administered to Abca4-/-Rdh8-/- mice with delayed clearance of atRAL that display light-induced and age-related retinal degeneration. The efficacy and metabolism of these drugs were examined by morphological and biochemical techniques.
More than 60% of tested amine drugs transiently lowered peak plasma concentrations of free atRAL and reduced retinal degeneration, and more than 40% did not affect chromophore regeneration in mice. Schiff base adducts between atRAL and these amines identified by mass spectrometry were observed in mouse eyes only when an experimental drug protected the retina from light-induced and age-related degeneration.
This study demonstrates the molecular basis of atRAL-induced retinal pathology and identifies a group of FDA-approved compounds that protect against this pathology in a mouse model that displays features of Stargardt’s and age-related retinal degeneration.
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