Document Detail


A1120, a nonretinoid RBP4 antagonist, inhibits formation of cytotoxic bisretinoids in the animal model of enhanced retinal lipofuscinogenesis.
MedLine Citation:
PMID:  23211825     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Excessive accumulation of lipofuscin is associated with pathogenesis of atrophic age-related macular degeneration (AMD) and Stargardt disease. Pharmacologic inhibition of the retinol-induced interaction of retinol-binding protein 4 (RBP4) with transthyretin (TTR) in the serum may decrease the uptake of serum retinol to the retina and reduce formation of lipofuscin bisretinoids. We evaluated in vitro and in vivo properties of the new nonretinoid RBP4 antagonist, A1120.
METHODS: RBP4 binding potency, ability to antagonize RBP4-TTR interaction, and compound specificity were analyzed for A1120 and for the prototypic RBP4 antagonist fenretinide. A1120 ability to inhibit RPE65-mediated isomerohydrolase activity was assessed in the RPE microsomes. The in vivo effect of A1120 administration on serum RBP4, visual cycle retinoids, lipofuscin bisretinoids, and retinal visual function was evaluated using a combination of biochemical and electrophysiologic techniques.
RESULTS: In comparison to fenretinide, A1120 did not act as a RARα agonist, while exhibiting superior in vitro potency in RBP4 binding and RBP4-TTR interaction assays. A1120 did not inhibit isomerohydrolase activity in the RPE microsomes. A1120 dosing in mice induced 75% reduction in serum RBP4, which correlated with reduction in visual cycle retinoids and ocular levels of lipofuscin fluorophores. A1120 dosing did not induce changes in kinetics of dark adaptation.
CONCLUSIONS: A1120 significantly reduces accumulation of lipofuscin bisretinoids in the Abca4(-/-) animal model. This activity correlates with reduction in serum RBP4 and visual cycle retinoids confirming the mechanism of action for A1120. In contrast to fenretinide, A1120 does not act as a RARα agonist indicating a more favorable safety profile for this nonretinoid compound.
Authors:
Nicoleta Dobri; Qiong Qin; Jian Kong; Kazunori Yamamoto; Zhao Liu; Gennadiy Moiseyev; Jian-Xing Ma; Rando Allikmets; Janet R Sparrow; Konstantin Petrukhin
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-07
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  54     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-08     Completed Date:  2013-03-05     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  85-95     Citation Subset:  IM    
Affiliation:
Department of Ophthalmology, Columbia University, New York, New York 10032, USA.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics
Animals
Antineoplastic Agents / metabolism,  pharmacology
Cattle
Disease Models, Animal
Fenretinide / pharmacology
Humans
Hydrolases / metabolism
Ligands
Lipofuscin / metabolism*
Macular Degeneration / drug therapy*,  metabolism,  pathology
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Mutant Strains
Piperidines / metabolism,  pharmacology*
Prealbumin / metabolism
Retinoids / metabolism*
Retinol-Binding Proteins, Plasma / antagonists & inhibitors*,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
P30 EY019007/EY/NEI NIH HHS; P30 EY019007/EY/NEI NIH HHS; R01 EY012951/EY/NEI NIH HHS; R01 EY012951/EY/NEI NIH HHS; R01 EY021163/EY/NEI NIH HHS; R21 NS067594/NS/NINDS NIH HHS; R24 EY019861/EY/NEI NIH HHS; R24 EY019861/EY/NEI NIH HHS; U01 NS074476/NS/NINDS NIH HHS; U01 NS074476/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/A1120 agent; 0/Abca4 protein, mouse; 0/Antineoplastic Agents; 0/Ligands; 0/Lipofuscin; 0/Piperidines; 0/Prealbumin; 0/RBP4 protein, human; 0/Rbp4 protein, mouse; 0/Retinoids; 0/Retinol-Binding Proteins, Plasma; 65646-68-6/Fenretinide; EC 3.-/Hydrolases
Comments/Corrections

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