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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Okano
authors.forename: Hideo
authors.initials: H
authors.lastname: Kohno
authors.forename: Satomi
authors.initials: S
authors.lastname: Shiose
authors.forename: Kaede
authors.initials: K
authors.lastname: Ishikawa
authors.forename: William
authors.initials: W
authors.lastname: Harte
authors.forename: Grazyna
authors.initials: G
authors.lastname: Palczewska
authors.forename: Tadao
authors.initials: T
authors.lastname: Maeda
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D000588:Amines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008268:Macular Degeneration / Q000188:drug therapy; D051379:Mice; D012162:Retinal Degeneration / Q000188:drug therapy / Q000517:prevention & control*; D012172:Retinaldehyde / Q000627:therapeutic use; D012545:Schiff Bases / Q000032:analysis; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000588:Amines; D012545:Schiff Bases; D012172:Retinaldehyde