醛糖还原酶抑制剂AL-1576对大鼠半乳糖性白内障的防治研究

Preventive effects of aldose reductase inhibitor AL-1576 on galactose cataract in rat

背景糖性白内障是糖尿病的主要眼部并发症之一，研究表明醛糖还原酶（AR）活性的升高与糖尿病的慢性并发症密切相关，是抗糖性白内障药物研究的重要靶点，其研究对糖性白内障的防治具有重要意义。目的探讨AR抑制剂AL-1576对半乳糖性白内障的防治效果和作用机制。方法4～5周龄SD大鼠42只，通过喂养质量分数50％半乳糖饲料制作半乳糖性白内障模型。大鼠按照随机数字表法平均分为7个组，AL-1576预防组，早、中、晚期治疗组在喂食50％半乳糖饲料的当天及5、10、15d后开始添加质量分数0．0125％AL-1576，另设空白对照组、模型对照组和AL-1576干预10d后撤除的早期撤药组。在裂隙灯显微镜下动态观察各组大鼠晶状体的混浊程度并进行分级，造模35d时摘出晶状体，分别测量其干质量、湿质量，计算并比较各组晶状体含水量的变化；检测造模35d时各组大鼠晶状体内AR活性、超氧化物歧化酶（SOD）活性以及谷胱甘肽（GSH）的含量。结果模型对照组大鼠12只眼晶状体均为Ⅳ级混浊，AL-1576预防组12只眼晶状体均透明，早期撤药组为Ⅱ-Ⅲ级混浊，早期治疗组为Ⅱ级混浊，而中期治疗组、晚期治疗组均为Ⅲ～Ⅳ级混浊，7个组晶状体混浊的程度差异均有统计学意义（H=17．760，P=0．009）。各AL-1576治疗组大鼠晶状体含水量、AR活性均比模型对照组明显降低，差异均有统计学意义（P〈0．05），但给药的时间越晚，晶状体含水量、AR活性降低的程度越小；各AL-1576治疗组大鼠晶状体SOD活性和GSH的含量明显高于模型对照组，差异均有统计学意义（P〈0．05），AL-1576预防组的升高幅度最大。结论在半乳糖性白内障形成的不同阶段给予AR抑制剂AL-1576可明显抑制AR的活性。AL-1576通过阻断和减轻晶状体水肿，提高晶状体的抗氧化能力，预防和延缓晶状体混浊的发生。

Background Sugar cataract is one of the major diabetic complications in the eye,but there is not effective medicine to prevent or delay development of cataract. Objective The goal of this study was to investigate the effects and the potential mechanism of aldose reductase （AR） inhibitor, AL-1576 on prevention of galaetose cataract in rats. Methods Forty-two SD rats were randomly and equally divided into 7 groups. The cataracts were induced by feeding with 50% galactose. At the day of feeding galactose and the day 5,10 and 15 after feeding galactose,AL-1576 was added into the feeds. The rats were divided AL-1576 prevention group and early-, intermediate-or late-stage intervention groups. For another group,the withdrawing AL-1576 group,AL-1576 was added into the feeds at the day of feeding galactose, then was removed after 10 days. The lenses of the rats were examined under the slit-lamp microscope before and after given AL-1576 every 5 days. At the day 35 ,the lenses were obtained. The wet and dry weight of the lenses were weighted, respectically, to calculate the water content of the lenses. Activities of AR and superoxidedismutase （SOD） and contents of glutathione （GSH） of the lenses were measured by their commercial detecting kits. The care and use of the animals complied with the Regulations for the Administration of Affairs Concerning Experimental Animals by State Science and Technology Commission. Results In AL-1576 prevention group,all lenses maintained clear. Opacification of the lenses were significantly attenuated in all three AL- 1576 intervention groups and withdrawing AL-1576 group compared with the cataractous model group （P〈0.05） ,but the inhibiting role was weaken with late intervention. The water contents and the activities of AR of the lenses were decreased,the contents of SOD and GSH were dramatically increased in all different AL-1576 treated groups compared with the cataractous model group （P〈0.05）. Moreover, AL-1576 prevention group showed the best effect on all indexes （P〈0.05）. Conclusions The activity of AR can be inhibited by AL-1576 at the different stages of development of cataract induced by galactose. By blocking and attenuating formation of the edema and elevating antioxdative capacity in the lenses,AL-1576 prevents and delays the formation of galaetose cataract.