Primary amines protect against retinal degeneration in mouse models of retinopathies

Akiko Maeda, Marcin Golczak, Yu Chen, Kiichiro Okano, Hideo Kohno, Satomi Shiose, Kaede Ishikawa, William Harte, Grazyna Palczewska, Tadao Maeda, Krzysztof Palczewski

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)170-178
Number of pages9
JournalNature Chemical Biology
Volume8
Issue number2
DOIs
Publication statusPublished - Feb 2012
Externally publishedYes

Fingerprint

Retinal Degeneration
Amines
Retinoids
United States Food and Drug Administration
Pathology
Regeneration
Retinaldehyde
Retinal Pigments
Schiff Bases
Poisons
Aldehydes
Pharmaceutical Preparations
Vertebrates
Retina
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Primary amines protect against retinal degeneration in mouse models of retinopathies. / Maeda, Akiko; Golczak, Marcin; Chen, Yu; Okano, Kiichiro; Kohno, Hideo; Shiose, Satomi; Ishikawa, Kaede; Harte, William; Palczewska, Grazyna; Maeda, Tadao; Palczewski, Krzysztof.

In: Nature Chemical Biology, Vol. 8, No. 2, 02.2012, p. 170-178.

Research output: Contribution to journalArticle

Maeda, A, Golczak, M, Chen, Y, Okano, K, Kohno, H, Shiose, S, Ishikawa, K, Harte, W, Palczewska, G, Maeda, T & Palczewski, K 2012, 'Primary amines protect against retinal degeneration in mouse models of retinopathies', Nature Chemical Biology, vol. 8, no. 2, pp. 170-178. https://doi.org/10.1038/nchembio.759
Maeda, Akiko ; Golczak, Marcin ; Chen, Yu ; Okano, Kiichiro ; Kohno, Hideo ; Shiose, Satomi ; Ishikawa, Kaede ; Harte, William ; Palczewska, Grazyna ; Maeda, Tadao ; Palczewski, Krzysztof. / Primary amines protect against retinal degeneration in mouse models of retinopathies. In: Nature Chemical Biology. 2012 ; Vol. 8, No. 2. pp. 170-178.
@article{c5e7503e29c14eae9a67db24dc6f39aa,
title = "Primary amines protect against retinal degeneration in mouse models of retinopathies",
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.",
author = "Akiko Maeda and Marcin Golczak and Yu Chen and Kiichiro Okano and Hideo Kohno and Satomi Shiose and Kaede Ishikawa and William Harte and Grazyna Palczewska and Tadao Maeda and Krzysztof Palczewski",
year = "2012",
month = "2",
doi = "10.1038/nchembio.759",
language = "English",
volume = "8",
pages = "170--178",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Primary amines protect against retinal degeneration in mouse models of retinopathies

AU - Maeda, Akiko

AU - Golczak, Marcin

AU - Chen, Yu

AU - Okano, Kiichiro

AU - Kohno, Hideo

AU - Shiose, Satomi

AU - Ishikawa, Kaede

AU - Harte, William

AU - Palczewska, Grazyna

AU - Maeda, Tadao

AU - Palczewski, Krzysztof

PY - 2012/2

Y1 - 2012/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84856110195&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856110195&partnerID=8YFLogxK

U2 - 10.1038/nchembio.759

DO - 10.1038/nchembio.759

M3 - Article

C2 - 22198730

AN - SCOPUS:84856110195

VL - 8

SP - 170

EP - 178

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 2

ER -