Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model
Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model
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DOI：
10.1016/s0014-2999(02)02793-0
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发表时间：
2003-01-05
影响因子：
5
通讯作者：
Kompella, UB
中科院分区：
文献类型：
--
作者：
Ayalasomayajula, SP;Kompella, UB
血管内皮生长因子（VEGF）的过度表达与糖尿病患者血管渗漏和视网膜新生血管的发生有关。本研究的目的是确定塞来昔布，一种选择性环氧合酶-2酶抑制剂，口服给药后是否到达眼组织，并抑制视网膜VEGF表达和血管渗漏在链脲佐菌素诱导的糖尿病大鼠模型。Sprague-Dawley大鼠单次腹腔注射链脲佐菌素（60 mg/kg）并确保在24 h结束时诱导糖尿病后，每日两次给予塞来昔布。经口灌胃（50 mg/kg）。在第8天，处死动物，测定视网膜VEGF和环氧合酶-2 mRNA水平、眼组织塞来昔布浓度和玻璃体/血浆蛋白比。在糖尿病大鼠中，视网膜VEGF mRNA表达是对照组的2.3倍，环氧合酶-2 mRNA表达相应增加。塞来昔布治疗可抑制VEGF mRNA表达，而环氧合酶-2 mRNA无任何显著降低。此外，糖尿病动物的视网膜血管渗漏估计为玻璃体与血浆蛋白的比值从0.35 +/- 0.1增加至1.1 +/- 0.1，塞来昔布治疗显著降低该比值至0.4 +/- 0.1。视网膜、玻璃体、透镜和角膜中的塞来昔布水平分别为24.8 ± 6.6、1.9 ± 1、1.7 ± 0.8和6.9 ± 0.9 ng/mg。血浆塞来昔布水平为85 +/- 24 ng/ml。因此，塞来昔布口服给药后可到达视网膜，并通过抑制环氧合酶-2的活性减少糖尿病诱导的视网膜VEGF mRNA表达和血管渗漏。(C)2002 Elsevier Science B. V.保留所有权利。
Overexpression of vascular endothelial growth factor (VEGF) is implicated in the development of vascular leakage and retinal neovascularization in diabetic subjects. The objective of this study was to determine whether celecoxib, a selective cyclooxygenase-2 enzyme inhibitor, reaches ocular tissues following oral administration and inhibits the retinal VEGF expression and vascular leakage in a streptozotocin-induced diabetic rat model. After administering a single intraperitoneal injection of streptozotocin (60 mg/kg) to Sprague-Dawley rats and ensuring the induction of diabetes at the end of 24 h, celecoxib was administered b.i.d. by oral gavage (50 mg/kg). On day 8, the animals were sacrificed and the retinal VEGF and cyclooxygenase-2 mRNA levels, ocular tissue celecoxib concentrations, and the vitreous/plasma protein ratio were determined. In diabetic rats, the retinal VEGF mRNA expression was 2.3-fold compared to controls, with a corresponding increase in cyclooxygenase-2 mRNA expression. Celecoxib treatment inhibited VEGF mRNA expression without any significant reduction in cyclooxygenase-2 mRNA. Furthermore, the retinal vascular leakage estimated as vitreous to plasma protein ratio increased in diabetic animals from 0.35 +/- 0.1 to 1.1 +/- 0.1 and celecoxib treatment significantly decreased this ratio to 0.4 +/- 0.1. Celecoxib levels were 24.8 +/- 6.6, 1.9 +/- 1, 1.7 +/- 0.8, and 6.9 +/- 0.9 ng/mg in the retina, vitreous, lens, and cornea, respectively. The plasma celecoxib levels were 85 +/- 24 ng/ml. Thus, celecoxib reaches the retina after oral administration and reduces diabetes-induced retinal VEGF mRNA expression and vascular leakage by inhibiting the activity of cyclooxygenase-2 enzyme. (C) 2002 Elsevier Science B.V. All rights reserved.