Ueno Y, Zhang N, Miyamoto N, Tanaka R, Hattori N, Urabe T
Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Neuroscience. 2009 Aug 18;162(2):317-27. doi: 10.1016/j.neuroscience.2009.04.065. Epub 2009 May 3.
A multicenter randomized clinical trial demonstrated that acute ischemic stroke patients treated with edaravone, a scavenger of hydroxyl radicals, had significant functional improvement. We tested the hypothesis that edaravone has protective effects against white matter lesions (WML) and endothelial injury, using a rat chronic hypoperfusion model. Adult Wistar rats underwent ligation of bilateral common carotid artery (LBCCA) and were divided into the edaravone group (injected once only immediately after LBCCA [n=39, ED(1)]; and injected on three consecutive days [n=39, ED(3)]), the vehicle group (n=39), and the sham group (n=15). Cerebral blood flow, Morris water maze performance, footprint test for locomotor function, immunohistochemical analyses and Western blot analysis were performed before and after LBCCA. The ED(3) group upregulated endothelial nitric oxide synthase and attenuated Evans Blue extravasation at day 3 after LBCCA (P<0.05). Edaravone markedly suppressed accumulation of 4-hydroxy-2-nonenal-modified protein and 8-hydroxy-deoxyguanosine (P<0.01), and loss of oligodendrocytes (P<0.05) in the cerebral white matter at days 3, 7, 14, 21 and 28 after LBCCA. These results were more evident in the ED(3) group. Moreover, at day 21 after LBCCA, spatial memory but not motor function, and axonal damage were significantly improved by three-time treatment of edaravone (P<0.05). Our results indicated that 3-day treatment with edaravone provides protection against WML through endothelial protection and free radical scavenging and suggested that edaravone is potentially useful for the treatment of cognitive impairment.
一项多中心随机临床试验表明，用依达拉奉（一种羟自由基清除剂）治疗的急性缺血性中风患者功能有显著改善。我们使用大鼠慢性低灌注模型，检验依达拉奉对白质病变（WML）和内皮损伤具有保护作用这一假设。成年Wistar大鼠接受双侧颈总动脉结扎（LBCCA），并分为依达拉奉组（仅在LBCCA后立即注射一次[n = 39，ED(1)]；连续三天注射[n = 39，ED(3)]）、溶剂对照组（n = 39）和假手术组（n = 15）。在LBCCA前后进行脑血流量、莫里斯水迷宫实验、运动功能足迹试验、免疫组织化学分析和蛋白质印迹分析。ED(3)组在LBCCA后第3天内皮型一氧化氮合酶上调，伊文思蓝外渗减轻（P<0.05）。依达拉奉在LBCCA后第3、7、14、21和28天显著抑制脑白质中4-羟基-2-壬烯醛修饰蛋白和8-羟基脱氧鸟苷的积累（P<0.01），以及少突胶质细胞的丢失（P<0.05）。这些结果在ED(3)组中更明显。此外，在LBCCA后第21天，依达拉奉三次治疗可显著改善空间记忆而非运动功能以及轴突损伤（P<0.05）。我们的结果表明，依达拉奉3天治疗通过内皮保护和自由基清除对白质病变提供保护，并提示依达拉奉对治疗认知障碍可能有用。
