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Primary amines protect against retinal degeneration in mouse models of retinopathies

Nature Chemical Biology volume 8, pages 170–178 (2012)Cite this article

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Abstract

Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore 11-cis-retinal and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomerized product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine–containing Food and Drug Administration (FDA)–approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by MS. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal–induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that shows features of Stargardt's disease and age-related retinal degeneration.

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Figure 1: Retinoid cycle and fate of atRAL in the retina.
Figure 2: Testing effects of amines on the development of acute light-induced retinal degeneration in Abca4−/− Rdh8−/− mice.
Figure 3: Effects of pre-administered amine drugs on light-induced acute retinal degeneration in 4-week-old Abca4−/− Rdh8−/− mice.
Figure 4: A20 stereoisomers protect against light-induced acute retinal degeneration in Abca4−/− Rdh8−/− mice.
Figure 5: Identification of retinal conjugates in retinas of Abca4−/− Rdh8−/− mice treated with A2 and A20.
Figure 6: Effects of treatment with amine drugs on age-related retinal degeneration in Abca4−/− Rdh8−/− mice.
Figure 7: Effects of preadministered amine drugs on light-induced retinal degeneration in BALB/c mice.

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Acknowledgements

We would like to thank Z. Dong for expert handling of mice, S. Roos for block preparation and plastic sectioning, J. Zhang for NMR analyses, and M. Matosky for retinoid analyses. We also thank L. Webster Jr, J. Saari, M.E. Maguire and members of the Palczewski laboratory for critical comments on the manuscript. This research was supported in part by grants EY009339, EY021126, EY019031, EY019880 and P30 EY11373 from the US National Institutes of Health; TECH 09–004 from the State of Ohio Department of Development; the Third Frontier Commission; Research to Prevent Blindness; Ohio Lion Eye Research Foundation; Foundation Fighting Blindness; and Fight for Sight.

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  1. Akiko Maeda and Marcin Golczak: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA

    Akiko Maeda & Tadao Maeda

  2. Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA

    Akiko Maeda, Marcin Golczak, Yu Chen, Kiichiro Okano, Hideo Kohno, Satomi Shiose, Kaede Ishikawa, Tadao Maeda & Krzysztof Palczewski

  3. Polgenix Inc., Cleveland, Ohio, USA

    William Harte

  4. Visum Inc., Cleveland, Ohio, USA

    Grazyna Palczewska

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Contributions

A.M., M.G. and K.P. conceived and directed the project. A.M., M.G., T.M., Y.C., K.O., H.K., S.S. and K.I. designed and conducted experiments. G.P. and K.P. performed pharmacological analyses of the data. A.M., M.G. and K.P. prepared the manuscript. A.M., M.G., G.P., W.H. and T.M. analyzed the data and edited the manuscript.

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Correspondence to Krzysztof Palczewski.

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Competing interests

Case Western Reserve University and Visum Inc. may commercialize some of the technology described in this work. A.M., M.G. and T.M. are consultants for Visum Inc., and K.P. and W.H. are cofounders of Visum Inc.

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Maeda, A., Golczak, M., Chen, Y. et al. Primary amines protect against retinal degeneration in mouse models of retinopathies. Nat Chem Biol 8, 170–178 (2012). https://doi.org/10.1038/nchembio.759

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