Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
PLoS One. 2011 Apr 26;6(4):e18980. doi: 10.1371/journal.pone.0018980.
Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation.
METHODS/PRINCIPAL FINDINGS: Proof of concept studies were conducted to evaluate 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), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.
CONCLUSIONS/SIGNIFICANCE: Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed.
年龄相关性白内障是一个全球性的健康问题，其进展与氧化应激和氧化还原活性金属的积累有关。由于没有特定的人类年龄相关性白内障的动物模型，因此必须使用多种动物模型来评估可能延迟和/或预防白内障形成的潜在疗法。
方法/主要发现：为了评估 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），这两种多官能抗氧化剂可以独立螯合氧化还原金属并淬灭自由基，进行了概念验证研究，以评估它们在延迟糖尿病“糖”白内障和γ辐射诱导白内障进展方面的能力。在进行全头部 15Gy 照射之前，选择长爪沙鼠的部分实验组接受含有化合物 4 或 8 的饮食，或单次腹腔注射泛硫乙胺，一种放射保护剂。与未处理、照射的大鼠相比，泛硫乙胺、4 和 8 分别延迟了初始晶状体变化 4、47 和 38 天，分别延迟了后囊下混浊的平均形成 23、53 和 58 天。在第二项研究中，选择部分糖尿病 Sprague Dawley 大鼠给予含有化合物 4、8 或醛糖还原酶抑制剂 AL1576 的饲料。如预期的那样，用 AL1576 治疗可通过抑制晶状体中山梨醇的形成来预防白内障。然而，与未处理的大鼠相比，化合物 4 和 8 分别延迟了空泡形成 20 天和 12 天，皮质白内障形成 8 天和 3 天，而不减少晶状体中山梨醇的含量。使用 30mM 木糖体外晶状体培养来模拟糖尿病“糖”白内障形成，Western blot 证实多官能抗氧化剂可减轻内质网应激。
结论/意义：多官能抗氧化剂在两种不同的大鼠模型中延迟了白内障的形成。这些研究提供了一个概念验证，即可以开发一种针对氧化应激而不是白内障发生机制的一般白内障治疗方法。
