Rota Rossella, Chiavaroli Carlo, Garay Ricardo P, Hannaert Patrick
Children's Hospital Bambino Gesu, IRCCS, Rome, Italy.
Eur J Pharmacol. 2004 Jul 14;495(2-3):217-24. doi: 10.1016/j.ejphar.2004.05.019.
Calcium dobesilate stabilizes blood-retinal barrier in patients with diabetic retinopathy and possesses antioxidant properties in the retinas of rats with streptozotocin-induced diabetes, exposed ex vivo to ischemia-reperfusion. Here we investigated the action of calcium dobesilate on retinal albumin leakage in streptozotocin-diabetic rats, together with relevant in vivo retinal antioxidant and permeability markers, i.e., carboxymethyl-lysine-advanced glycation end product (CML-AGE) formation and vascular endothelial cell growth factor (VEGF) overexpression. Twenty days after streptozotocin administration, diabetic rats were treated for 10 days with calcium dobesilate (100 mg/kg/day per os) or vehicle. Retinal albumin leakage, CML-AGE formation, and VEGF overexpression were evaluated by immunohistochemistry of frozen eye sections. Diabetic rats exhibited dramatic increases in: (i) retinal albumin leakage (31% of positive vessels vs. 0.2% in nondiabetic rats, P<0.008), (ii) CML-AGE retinal occurrence (40+/-3% vs. undetectable positive vessels), and (iii) retinal VEGF protein expression (14.6+/-1.1 vs. 3.5+/-0.5 VEGF-positive spots/field, P<10(-4)). Calcium dobesilate significantly reduced: (i) retinal albumin leakage (by 70%, P<0.008), (ii) retinal CML-AGEs contents (by 62%, P<0.008), and (iii) retinal VEGF expression (by 69.4%, P<0.008). In conclusion, calcium dobesilate orally given to diabetic rats markedly reduced retinal hyperpermeability, CML-AGE contents, and VEGF overexpression. These results strongly suggest that calcium dobesilate stabilizes blood-retinal barrier in diabetic retinopathy via an in situ antioxidant action. Further studies in patients are required to confirm such view.
羟苯磺酸钙可稳定糖尿病视网膜病变患者的血视网膜屏障，并在链脲佐菌素诱导的糖尿病大鼠视网膜中具有抗氧化特性，这些大鼠的视网膜在体外经历了缺血再灌注。在此，我们研究了羟苯磺酸钙对链脲佐菌素诱导的糖尿病大鼠视网膜白蛋白渗漏的作用，以及相关的体内视网膜抗氧化和通透性标志物，即羧甲基赖氨酸-晚期糖基化终产物（CML-AGE）的形成和血管内皮生长因子（VEGF）的过表达。链脲佐菌素给药20天后，糖尿病大鼠用羟苯磺酸钙（100mg/kg/天，口服）或赋形剂治疗10天。通过冰冻眼切片的免疫组织化学评估视网膜白蛋白渗漏、CML-AGE的形成和VEGF的过表达。糖尿病大鼠表现出显著增加：（i）视网膜白蛋白渗漏（阳性血管占31%，而非糖尿病大鼠为0.2%，P<0.008），（ii）CML-AGE在视网膜中的出现（40±3%，而未检测到阳性血管），以及（iii）视网膜VEGF蛋白表达（14.6±1.1对3.5±0.5个VEGF阳性斑点/视野，P<10-4）。羟苯磺酸钙显著降低：（i）视网膜白蛋白渗漏（降低70%，P<0.008），（ii）视网膜CML-AGEs含量（降低62%，P<0.008），以及（iii）视网膜VEGF表达（降低69.4%，P<0.008）。总之，给糖尿病大鼠口服羟苯磺酸钙可显著降低视网膜高通透性、CML-AGE含量和VEGF过表达。这些结果强烈表明，羟苯磺酸钙通过原位抗氧化作用稳定糖尿病视网膜病变中的血视网膜屏障。需要对患者进行进一步研究以证实这一观点。
