IOVS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1167/iovs.09-3581 on June 3, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:4917-4925.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3581
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
iovs.09-3581v1
50/10/4917    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Maeda, T.
Right arrow Articles by Palczewski, K.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maeda, T.
Right arrow Articles by Palczewski, K.

Evaluation of Potential Therapies for a Mouse Model of Human Age-Related Macular Degeneration Caused by Delayed all-trans-Retinal Clearance

Tadao Maeda,1,2,3 Akiko Maeda,1,2,3 Melissa Matosky,1 Kiichiro Okano,1 Satsumi Roos,1 Johnny Tang,2,4 and Krzysztof Palczewski1

1From the Departments of Pharmacology and 2Ophthalmology, Case Western Reserve University, Cleveland, Ohio; and the 4Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio.

PURPOSE. Evaluate the efficacy of potential therapeutics in Rdh8–/–Abca4–/– mice, a rodent model of human age-related macular degeneration (AMD).

METHODS. Therapeutic efficacy of several antioxidant agents (ascorbic acid, {alpha}-lipoic acid, {alpha}-tocopherol, Mn(III)-tetrakis(4-benzoic acid)-porphyrin, and butylated hydroxytoluene), an immunosuppressive agent with antivascular endothelial growth factor (VEGF) activity (sirolimus, also known as rapamycin), a retinoid cycle inhibitor (retinylamine), and an artificial chromophore (9-cis-retinyl acetate) were evaluated side by side in a recently described murine model of AMD, the Rdh8–/–Abca4–/– mouse. This animal exhibits a retinopathy caused by delayed all-trans-retinal clearance resulting from the absence of both ATP-binding cassette transporter 4 (Abca4) and retinol dehydrogenase 8 (Rdh8) activities. Drug efficacy was evaluated by retinal histologic analyses and electroretinograms (ERGs).

RESULTS. All tested agents partially prevented atrophic changes in the Rdh8–/–Abca4–/– retina with retinylamine demonstrating the greatest efficacy. A significant reduction of complement deposition on Bruch’s membrane was observed in sirolimus-treated mice, although the severity of retinal degeneration was similar to that observed in antioxidant- and 9-cis-retinyl acetate–treated mice. Sirolimus treatment of 6-month-old Rdh8–/–Abca4–/– mice for 4 months prevented choroidal neovascularization without changing retinal VEGF levels.

CONCLUSIONS. Mechanism-based therapy with retinylamine markedly attenuated degenerative retinopathy in Rdh8–/–Abca4–/– mice. Further understanding of pathogenic mechanisms involved in AMD is needed to develop more effective therapeutics.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2009 by the Association for Research in Vision and Ophthalmology