Sun Wei, Gerhardinger Chiara, Dagher Zeina, Hoehn Todd, Lorenzi Mara
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, Massachusetts 02114, USA.
Diabetes. 2005 Dec;54(12):3418-26. doi: 10.2337/diabetes.54.12.3418.
The prevention of diabetic retinopathy requires drugs that leverage the benefits of glycemic control without adding the burden of side effects. Aspirin at dosages of 1-1.5 g/day has prevented manifestations of diabetic retinal microangiopathy in a clinical trial as well as in studies with dogs. Because lower and safer doses of aspirin could be used if its beneficial effects on retinopathy were due to antithrombotic effects, we compared the effects of a selective antiplatelet drug (clopidogrel) to those of aspirin in streptozotocin-induced diabetic rats. Clopidogrel did not prevent neuronal apoptosis, glial reactivity, capillary cell apoptosis, or acellular capillaries in the retina of diabetic rats. Aspirin, at doses yielding serum levels (<0.6 mmol/l) well below the anti-inflammatory range for humans, prevented apoptosis of capillary cells and the development of acellular capillaries but did not prevent neuroglial abnormalities. The aldose reductase inhibitor sorbinil, used as the benchmark for the effect of the other drugs, prevented all abnormalities. The diabetic rat retina showed increased expression of the transcription factor CCAAT/enhancer-binding protein-beta, one of the known targets of low-intermediate concentrations of aspirin. Thus we found a spectrum of drug efficacy on the prevention of experimental diabetic retinopathy, ranging from the absent effect of a selective antiplatelet drug to the prevention of all abnormalities by an aldose reductase inhibitor. Aspirin at low-intermediate concentrations selectively prevented microangiopathy. The minimal effective dose of aspirin should now be sought.
预防糖尿病视网膜病变需要既能利用血糖控制的益处又不增加副作用负担的药物。在一项临床试验以及对狗的研究中，每天服用1 - 1.5克剂量的阿司匹林可预防糖尿病视网膜微血管病变的表现。如果阿司匹林对视网膜病变的有益作用是由于抗血栓作用，那么就可以使用更低且更安全的剂量，因此我们在链脲佐菌素诱导的糖尿病大鼠中比较了选择性抗血小板药物（氯吡格雷）与阿司匹林的作用。氯吡格雷不能预防糖尿病大鼠视网膜中的神经元凋亡、神经胶质反应、毛细血管细胞凋亡或无细胞毛细血管的形成。阿司匹林在产生远低于人类抗炎范围的血清水平（<0.6 mmol/l）的剂量下，可预防毛细血管细胞凋亡和无细胞毛细血管的形成，但不能预防神经胶质异常。醛糖还原酶抑制剂索比尼尔用作其他药物效果的基准，可预防所有异常。糖尿病大鼠视网膜显示转录因子CCAAT/增强子结合蛋白β的表达增加，该蛋白是低 - 中等浓度阿司匹林的已知靶点之一。因此我们发现了一系列药物对预防实验性糖尿病视网膜病变的疗效，从选择性抗血小板药物的无效作用到醛糖还原酶抑制剂预防所有异常。低 - 中等浓度的阿司匹林选择性地预防了微血管病变。现在应该寻找阿司匹林的最小有效剂量。
