Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China.
J Clin Neurosci. 2010 Nov;17(11):1407-11. doi: 10.1016/j.jocn.2010.03.041. Epub 2010 Aug 21.
Previous studies have demonstrated that mitogen-activated protein kinase (MAPK) is involved in the pathogenesis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Ras, an upstream regulator of MAPK, may be activated following SAH. The aim of this study was to investigate the role of Ras in cerebral vasospasm in a rabbit model of SAH. We first investigated the time course of Ras and ERK1/2 activation in the basilar artery after SAH. Next, for the time point at which Ras was maximally activated, we assessed the effect of FTI-277 (a Ras farnesyltransferase inhibitor) on cerebral vasospasm. SAH was induced by injecting autologous blood into the cisterna magna on both day 0 and day 2. FTI-277 was injected into the cisterna magna every 24 hours, beginning 30 minutes after blood injection to the last day of the experiment. Elevated expression of Ras-GTP and phosphorylated ERK1/2 was detected in the basilar artery after SAH and expression peaked on day 3. FTI-277 administration resulted in lower Ras-GTP and phosphorylated ERK1/2 levels and markedly attenuated vasospasm in the basilar arteries relative to animals that did not receive FTI-277. Our results suggest that Ras protein is activated in the arterial wall after SAH and contributes to vasospasm development.
先前的研究表明，丝裂原活化蛋白激酶（MAPK）参与了蛛网膜下腔出血（SAH）后脑血管痉挛的发病机制。MAPK 的上游调节因子 Ras，可能会在 SAH 后被激活。本研究旨在探讨 Ras 在兔 SAH 模型中对脑血管痉挛的作用。我们首先研究了 SAH 后基底动脉中 Ras 和 ERK1/2 激活的时间过程。接下来，针对 Ras 被最大程度激活的时间点，我们评估了 FTI-277（一种 Ras 法呢基转移酶抑制剂）对脑血管痉挛的影响。通过在第 0 天和第 2 天向两侧脑池内注入自体血来诱导 SAH。FTI-277 于注血后 30 分钟开始每 24 小时注入脑池一次，直至实验的最后一天。SAH 后基底动脉中 Ras-GTP 和磷酸化 ERK1/2 的表达升高，表达在第 3 天达到峰值。FTI-277 给药导致 Ras-GTP 和磷酸化 ERK1/2 水平降低，并显著减轻基底动脉的血管痉挛，与未接受 FTI-277 的动物相比。我们的结果表明，Ras 蛋白在 SAH 后动脉壁中被激活，并有助于血管痉挛的发展。
