Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
PLoS One. 2011;6(7):e21926. doi: 10.1371/journal.pone.0021926. Epub 2011 Jul 14.
Progression of age-related macular degeneration has been linked to iron dysregulation and oxidative stress that induce apoptosis of neural retinal cells. Since both antioxidants and chelating agents have been reported to reduce the progression of retinal lesions associated with AMD in experimental animals, the present study evaluates the ability of multi-functional antioxidants containing functional groups that can independently chelate redox metals and quench free radicals to protect the retina against light-induced retinal degeneration, a rat model of dry atrophic AMD.
METHODS/RESULTS: Proof of concept studies were conducted to evaluate the ability of 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8) to reduce retinal damage in 2-week dark adapted Wistar rats exposed to 1000 lx of light for 3 hours. Assessment of the oxidative stress markers 4- hydroxynonenal and nitrotyrosine modified proteins and Thioredoxin by ELISA and Western blots indicated that these compounds reduced the oxidative insult caused by light exposure. The beneficial antioxidant effects of these compounds in providing significant functional and structural protection were confirmed by electroretinography and quantitative histology of the retina.
CONCLUSIONS/SIGNIFICANCE: The present study suggests that multi-functional compounds may be effective candidates for preventive therapy of AMD.
年龄相关性黄斑变性的进展与铁失调和氧化应激有关，这些因素会诱导神经视网膜细胞凋亡。由于抗氧化剂和螯合剂已被报道能减少实验动物中与 AMD 相关的视网膜病变的进展，因此本研究评估了含有能独立螯合氧化还原金属和淬灭自由基的功能基团的多功能抗氧化剂，以保护视网膜免受光诱导的干性萎缩性 AMD 大鼠模型的视网膜变性。
方法/结果：进行概念验证研究，以评估 4-(5-羟嘧啶-2-基)-N,N-二甲基-3,5-二氧代哌嗪-1-磺酰胺（化合物 4）和 4-(5-羟基-4,6-二甲氧基嘧啶-2-基)-N,N-二甲基-3,5-二氧代哌嗪-1-磺酰胺（化合物 8）减少在 1000 lx 的光下暴露 3 小时的 2 周暗适应 Wistar 大鼠的视网膜损伤的能力。通过 ELISA 和 Western blot 评估氧化应激标志物 4-羟壬烯醛和硝基酪氨酸修饰蛋白和硫氧还蛋白，表明这些化合物减轻了光暴露引起的氧化损伤。这些化合物在提供显著的功能和结构保护方面的有益抗氧化作用通过视网膜的视网膜电图和定量组织学得到证实。
结论/意义：本研究表明，多功能化合物可能是 AMD 预防治疗的有效候选物。
