Effects of long-term administration of 9-cis-retinyl acetate on visual function in mice.
OBJECTIVE
Long-term effects of treatment with 9-cis-retinyl acetate (9-cis-R-Ac), an artificial retinoid prodrug, were tested on changes in rod and cone visual functions in mice.


METHODS
The acetyl ester of the functional geometric chromophore 9-cis-retinal was delivered by oral gavage to C57BL/6 female mice. In initial experiments, 10-month-old mice were used for the single treatment with 9-cis-R-Ac or the control vehicle. In long-term experiments, 4-month-old mice were treated with 9-cis-R-Ac monthly for 6 and 10 months. Photoreceptor status was evaluated by various electroretinographic (ERG) techniques, retinoid analyses, and retinal morphology. Opsin, the predicted target of oxidized 9-cis-R-Ac, was purified and its chromophore was characterized.


RESULTS
Age-related changes observed in vehicle-treated mice at 10 months of age, compared with those in 4-month-old mice, included a progressive decline in ERG responses, such as a decreased rate of dark adaptation and a lowered rhodopsin/opsin ratio. Administration of 9-cis-R-Ac increased the rhodopsin regeneration ratio, and improved ERG responses and dark adaptation. Compared with vehicle-treated control animals, 10- and 14-month-old mice treated monthly with 9-cis-R-Ac for 6 or 10 months exhibited improved dark adaptation. In 14-month-old mice treated monthly, changes in the expression of retina-specific genes in the eye were detected by mRNA expression profiling, but no significant effects in gene expression were detected in the liver and kidney.


CONCLUSIONS
Deteriorating photoreceptor function documented in mice at 10 and 14 versus 4 months of age was improved significantly by long-term, monthly administration of 9-cis-R-Ac. These findings suggest a potential therapeutic approach to prevent age-related retinal dysfunction.
Maeda
Tadao
T
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA. txm88@case.edu
Maeda
Akiko
A
Leahy
Patrick
P
Saperstein
David A
DA
Palczewski
Krzysztof
K
D000284:Administration, Oral; D000375:Aging / Q000502:physiology*; D000818:Animals; D003623:Dark Adaptation / Q000502:physiology; D004224:Diterpenes; D004596:Electroretinography; D005260:Female; D020869:Gene Expression Profiling; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D055355:Opsins / Q000378:metabolism; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology*; D011355:Prodrugs / Q000008:administration & dosage*; D012313:RNA / Q000235:genetics; D012176:Retinoids / Q000378:metabolism; D000084562:Retinyl Esters; D012243:Rhodopsin / Q000378:metabolism; D014801:Vitamin A / Q000008:administration & dosage / Q000031:analogs & derivatives*
D004224:Diterpenes; D055355:Opsins; D011355:Prodrugs; D012176:Retinoids; D000084562:Retinyl Esters; D014801:Vitamin A; C009166:retinol acetate; D012313:RNA; D012243:Rhodopsin