Kern Timothy S, Miller Casey M, Du Yunpeng, Zheng Ling, Mohr Susanne, Ball Sherry L, Kim M, Jamison Jeffrey A, Bingaman David P
Medicine and Ophthalmology, 434 Biomedical Research Building, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA.
Diabetes. 2007 Feb;56(2):373-9. doi: 10.2337/db05-1621.
Pharmacologic treatment of diabetic retinopathy via eyedrops could have advantages but has not been successful to date. We explored the effect of topical Nepafenac, an anti-inflammatory drug known to reach the retina when administered via eyedrops, on the development of early stages of diabetic retinopathy and on metabolic and physiologic abnormalities that contribute to the retinal disease. Streptozotocin-induced diabetic rats were assigned to three groups (0.3% Nepafenac eyedrops, vehicle eyedrops, and untreated control) for comparison to age-matched nondiabetic control animals. Eyedrops were administered in both eyes four times per day for 2 and 9 months. At 2 months of diabetes, insulin-deficient diabetic control rats exhibited significant increases in retinal prostaglandin E(2), superoxide, vascular endothelial growth factor (VEGF), nitric oxide (NO), cyclooxygenase-2, and leukostasis within retinal microvessels. All of these abnormalities except NO and VEGF were significantly inhibited by Nepafenac. At 9 months of diabetes, a significant increase in the number of transferase-mediated dUTP nick-end labeling-positive capillary cells, acellular capillaries, and pericyte ghosts were measured in control diabetic rats versus nondiabetic controls, and topical Nepafenac significantly inhibited all of these abnormalities (all P < 0.05). Diabetes-induced activation of caspase-3 and -6 in retina was partially inhibited by Nepafenac (all P < 0.05). Oscillatory potential latency was the only abnormality of retinal function reproducibly detected in these diabetic animals, and Nepafenac significantly inhibited this defect (P < 0.05). Nepafenac did not have a significant effect on diabetes-induced loss of cells in the ganglion cell layer or in corneal protease activity. Topical ocular administration of Nepafenac achieved sufficient drug delivery to the retina and diabetes-induced alterations in retinal vascular metabolism, function, and morphology were inhibited. In contrast, little or no effect was observed on diabetes-induced alterations in retinal ganglion cell survival. Local inhibition of inflammatory pathways in the eye offers a novel therapeutic approach toward inhibiting the development of lesions of diabetic retinopathy.
通过眼药水对糖尿病性视网膜病变进行药物治疗可能具有优势，但迄今为止尚未取得成功。我们探讨了局部应用萘帕芬酸（一种已知通过眼药水给药时可到达视网膜的抗炎药物）对糖尿病性视网膜病变早期发展以及对导致视网膜疾病的代谢和生理异常的影响。将链脲佐菌素诱导的糖尿病大鼠分为三组（0.3%萘帕芬酸眼药水组、赋形剂眼药水组和未治疗对照组），与年龄匹配的非糖尿病对照动物进行比较。每天双眼滴眼药水四次，持续2个月和9个月。糖尿病2个月时，胰岛素缺乏的糖尿病对照大鼠视网膜前列腺素E(2)、超氧化物、血管内皮生长因子（VEGF）、一氧化氮（NO）、环氧化酶-2以及视网膜微血管内白细胞淤滞均显著增加。除NO和VEGF外，所有这些异常均被萘帕芬酸显著抑制。糖尿病9个月时，与非糖尿病对照相比，对照糖尿病大鼠中转氨酶介导的dUTP缺口末端标记阳性毛细血管细胞、无细胞毛细血管和周细胞鬼影数量显著增加，局部应用萘帕芬酸显著抑制了所有这些异常（所有P<0.05）。萘帕芬酸部分抑制了糖尿病诱导的视网膜中caspase-3和-6的激活（所有P<0.05）。振荡电位潜伏期是在这些糖尿病动物中可重复检测到的唯一视网膜功能异常，萘帕芬酸显著抑制了这一缺陷（P<0.05）。萘帕芬酸对糖尿病诱导的神经节细胞层细胞丢失或角膜蛋白酶活性没有显著影响。局部眼部应用萘帕芬酸可实现足够的药物输送至视网膜，并且抑制了糖尿病诱导的视网膜血管代谢、功能和形态改变。相比之下，对糖尿病诱导的视网膜神经节细胞存活改变几乎没有影响。眼部炎症途径的局部抑制为抑制糖尿病性视网膜病变病变发展提供了一种新的治疗方法。
