Topical Administration of Bosentan Prevents Retinal Neurodegeneration in Experimental Diabetes.
Topical Administration of Bosentan Prevents Retinal Neurodegeneration in Experimental Diabetes.
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DOI：
10.3390/ijms19113578
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发表时间：
2018-11-13
影响因子：
5.6
通讯作者：
Simó R
中科院分区：
文献类型：
--
作者：
Bogdanov P;Simó-Servat O;Sampedro J;Solà-Adell C;Garcia-Ramírez M;Ramos H;Guerrero M;Suñé-Negre JM;Ticó JR;Montoro B;Durán V;Arias L;Hernández C;Simó R
实验证据表明，内皮素1 （ET-1）参与糖尿病所致视网膜微血管异常的发生。ET-1的作用是由内皮素A和b受体（ETA和ETB）介导的。内皮素b受体激活介导视网膜神经退行性变，但目前尚无关于内皮素b受体阻断在阻止糖尿病引起的视网膜神经退行性变中的有效性的数据。本研究的主要目的是评估局部给药波生坦（一种双重内皮素受体拮抗剂）在预防糖尿病（db/db）小鼠视网膜神经变性方面的有效性。为此，10周龄的db/db小鼠接受1滴波生坦（5mg /mL, n = 6）或对照剂（n = 6）治疗，每天两次，持续14天。6只与年龄匹配的非糖尿病（db/+）小鼠作为对照组。利用抗胶质纤维酸性蛋白（GFAP）特异性抗体免疫荧光法评估胶质细胞活化。TUNEL法检测细胞凋亡。在家兔体内进行了药代动力学研究。我们发现局部给药波生坦导致反应性胶质瘤和细胞凋亡的显著减少。药代动力学研究结果提示波生坦通过经巩膜途径到达视网膜。我们的结论是，局部施用波生坦在预防糖尿病视网膜神经变性方面是有效的，因此可以在临床试验中进行测试。
Experimental evidence suggests that endothelin 1 (ET-1) is involved in the development of retinal microvascular abnormalities induced by diabetes. The effects of ET-1 are mediated by endothelin A- and B-receptors (ETA and ETB). Endothelin B-receptors activation mediates retinal neurodegeneration but there are no data regarding the effectiveness of ETB receptor blockage in arresting retinal neurodegeneration induced by diabetes. The main aim of the present study was to assess the usefulness of topical administration of bosentan (a dual endothelin receptor antagonist) in preventing retinal neurodegeneration in diabetic (db/db) mice. For this purpose, db/db mice aged 10 weeks were treated with one drop of bosentan (5 mg/mL, n = 6) or vehicle (n = 6) administered twice daily for 14 days. Six non-diabetic (db/+) mice matched by age were included as the control group. Glial activation was evaluated by immunofluorescence using specific antibodies against glial fibrillary acidic protein (GFAP). Apoptosis was assessed by TUNEL method. A pharmacokinetic study was performed in rabbits. We found that topical administration of bosentan resulted in a significant decrease of reactive gliosis and apoptosis. The results of the pharmacokinetic study suggested that bosentan reached the retina through the trans-scleral route. We conclude that topical administration of bosentan was effective in preventing neurodegeneration in the diabetic retina and, therefore, could be a good candidate to be tested in clinical trials.
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影响因子：
37.8
作者：
Lüscher, TF;Barton, M
通讯作者：
Barton, M
影响因子：
8.2
作者：
De Juan, JA;Moya, FJ;Fernandez-Durango, R
通讯作者：
Fernandez-Durango, R
影响因子：
3.7
作者：
Minton AZ;Phatak NR;Stankowska DL;He S;Ma HY;Mueller BH;Jiang M;Luedtke R;Yang S;Brownlee C;Krishnamoorthy RR
通讯作者：
Krishnamoorthy RR
影响因子：
2.9
作者：
Kalani M
通讯作者：
Kalani M
影响因子：
17.8
作者：
Simo, Rafael;Hernandez, Cristina
通讯作者：
Hernandez, Cristina