Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, 505 Banpo-dong, Seocho-ku, Seoul 137-701, Korea.
J Pharmacol Exp Ther. 2013 Jun;345(3):457-63. doi: 10.1124/jpet.113.203067. Epub 2013 Mar 27.
Neurodegeneration is an important component of diabetic retinopathy, with increasing evidence that retinal ganglion cell (RGC) death occurs early in diabetes. We investigated the effects of cilostazol, which has been widely used to manage diabetic complications, on retinal ganglion cell death in the diabetic retina. Four-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats as matched nondiabetic controls were treated with daily oral cilostazol at 30 mg/kg or 0.9% saline solution. In OLETF rats at the age of 40 weeks, glial fibrillary acidic protein (GFAP) immunofluorescence staining was upregulated in vertical sections, and showed a more ramified pattern in whole-mount retinas compared with that in LETO rats. Vascular endothelial growth factor (VEGF) expression was limited to the ganglion cell layer in LETO rats, but extended into the outer plexiform layer in OLETF rats. Immunofluorescence staining and Western blotting demonstrated that cilostazol treatment reduced GFAP and VEGF expression in the retinas of OLETF rats. Terminal deoxynucleotidyl transferase-mediated terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL) staining revealed an increase in the RGC layer in OLETF compared with LETO rats (P < 0.05), and cilostazol treatment reduced the number of TUNEL-positive cells in OLETF rats (P < 0.05). Relieving retinal ischemia by systemic cilostazol treatment had a noticeable protective effect on RGCs in diabetic rats. Cilostazol treatment may be useful for the management of diabetic retinal vascular dysfunction and neuronal degeneration.
神经退行性变是糖尿病性视网膜病变的一个重要组成部分，越来越多的证据表明，视网膜神经节细胞（RGC）死亡发生在糖尿病的早期。我们研究了西洛他唑的作用，西洛他唑已被广泛用于治疗糖尿病并发症，观察其对糖尿病视网膜中 RGC 死亡的影响。4 周龄的大冢长野肥胖（OLETF）大鼠和长野长野大冢（LETO）大鼠作为匹配的非糖尿病对照，每日口服西洛他唑 30mg/kg 或 0.9%生理盐水溶液。在 40 周龄的 OLETF 大鼠中，胶质纤维酸性蛋白（GFAP）免疫荧光染色在垂直切片中上调，并且与 LETO 大鼠相比，在整个视网膜中呈现出更分支的模式。血管内皮生长因子（VEGF）表达在 LETO 大鼠中仅限于节细胞层，但在 OLETF 大鼠中延伸到外丛状层。免疫荧光染色和 Western blot 表明，西洛他唑治疗降低了 OLETF 大鼠视网膜中的 GFAP 和 VEGF 表达。末端脱氧核苷酸转移酶介导的末端脱氧核苷酸转移酶介导的地高辛-脱氧尿苷尼克末端标记（TUNEL）染色显示 OLETF 大鼠的 RGC 层比 LETO 大鼠增加（P<0.05），西洛他唑治疗减少了 OLETF 大鼠中 TUNEL 阳性细胞的数量（P<0.05）。通过全身西洛他唑治疗缓解视网膜缺血对糖尿病大鼠的 RGC 具有明显的保护作用。西洛他唑治疗可能对糖尿病视网膜血管功能障碍和神经元变性的治疗有用。
