Maeda Tadao, Maeda Akiko, Leahy Patrick, Saperstein David A, Palczewski Krzysztof
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA.
Invest Ophthalmol Vis Sci. 2009 Jan;50(1):322-33. doi: 10.1167/iovs.08-2301. Epub 2008 Aug 15.
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.
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.
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.
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.
测试人工类视黄醇前药9-顺式视黄酸醋酸酯（9-cis-R-Ac）治疗对小鼠视杆和视锥视觉功能变化的长期影响。
通过口服灌胃将功能性几何发色团9-顺式视黄醛的乙酰酯给予C57BL/6雌性小鼠。在初始实验中，10月龄小鼠接受9-cis-R-Ac或对照载体的单次治疗。在长期实验中，4月龄小鼠每月接受9-cis-R-Ac治疗，持续6个月和10个月。通过各种视网膜电图（ERG）技术、类视黄醇分析和视网膜形态学评估光感受器状态。视蛋白是氧化型9-cis-R-Ac的预测靶点，对其进行了纯化并对其发色团进行了表征。
与4月龄小鼠相比，10月龄载体处理小鼠中观察到的与年龄相关的变化包括ERG反应逐渐下降，如暗适应率降低和视紫红质/视蛋白比率降低。给予9-cis-R-Ac可提高视紫红质再生率，并改善ERG反应和暗适应。与载体处理的对照动物相比，每月接受9-cis-R-Ac治疗6个月或10个月的10月龄和14月龄小鼠表现出改善的暗适应。在每月接受治疗的14月龄小鼠中，通过mRNA表达谱检测到眼睛中视网膜特异性基因表达的变化，但在肝脏和肾脏中未检测到基因表达的显著影响。
长期每月给予9-cis-R-Ac可显著改善10月龄和14月龄与4月龄小鼠相比记录到的光感受器功能恶化。这些发现提示了一种预防年龄相关性视网膜功能障碍的潜在治疗方法。
