Simvastatin attenuates cerebral vasospasm and improves outcomes by upregulation of PI3K/Akt pathway in a rat model of subarachnoid hemorrhage.
Simvastatin attenuates cerebral vasospasm and improves outcomes by upregulation of PI3K/Akt pathway in a rat model of subarachnoid hemorrhage.
复制标题
在蛛网膜下腔出血大鼠模型中，辛伐他汀通过上调 PI3K/Akt 通路来减轻脑血管痉挛并改善预后。
DOI：
10.1007/978-3-211-85578-2_76
复制
发表时间：
2008
期刊：
影响因子：
--
通讯作者：
John H. Zhang
中科院分区：
文献类型：
--
作者：
T. Sugawara;V. Jadhav;R. Ayer;John H. Zhang
背景
脑血管痉挛是蛛网膜下腔出血（SAH）的常见后遗症，但其发生机制尚不清楚。最近，他汀类药物已被证明具有改善脑血管痉挛的疗效。本研究探讨辛伐他汀是否通过上调PI 3 K/Akt通路减轻蛛网膜下腔出血（SAH）后的脑血管痉挛。
方法
47只成年雄性Sprague-Dawley大鼠分为6组：假手术组、SAH溶剂组、SAH低剂量辛伐他汀（1 mg/kg）组、高剂量辛伐他汀（20 mg/kg）组、SAH辛伐他汀+PI 3 K抑制剂（渥曼青霉素）组、假手术+渥曼青霉素组。通过标准血管内穿孔模型建立SAH后30分钟，腹腔内给予辛伐他汀。在24小时评估同侧颈内动脉的组织学参数（ICA直径、周长和壁厚）和神经学评分。
结果
两个给药组的死亡率均降至零，相比之下，溶媒给药组为20%，辛伐他汀+渥曼青霉素给药组为36%。在溶剂处理组中观察到伊卡直径和周长减小与假手术组（259.7 +/- 10.6，865.4 +/- 39.5）相比，高剂量辛伐他汀（267.4 +/- 8.0，882.4 +/- 30.0）显著减弱了（203.2 +/- 10.3 microm，652.7 +/- 29.0 microm）。高剂量和低剂量辛伐他汀（11.87 +/- 1.56，19.75 +/- 1.40）均显著减弱了室壁厚度的增加（溶剂组29.50 +/- 2.42 μ m，假手术组9.52 +/- 0.56 μ m）。辛伐他汀的这些作用在添加渥曼青霉素后被阻断（162.7 +/- 20.6，528.9 +/- 65.9，29.19 +/- 1.97）。大剂量辛伐他汀可改善SAH后的神经功能缺损，但这一作用也被渥曼青霉素阻断。
结论
高剂量辛伐他汀改善脑血管痉挛的有益作用可能是通过上调PI 3 K/Akt通路介导的。
BACKGROUND
Cerebral vasospasm is a common sequelae of subarachonoid hemorrhage (SAH), however, the mechanism of cerebral vasospasm is still unclear. Recently, statins have been shown to have efficacy in ameliorating cerebral vasospasm. The present study investigates whether simvastatin attenuates cerebral vasospasm after subarachnoid hemorrhage (SAH) via upregulation of the PI3K/Akt pathway.
METHODS
47 adult male Sprague-Dawley rats were divided into 6 groups: sham-operated, SAH treated with vehicle, SAH treated with low dose simvastatin (1 mg/kg), high dose simvastatin (20 mg/kg), SAH treated with simvastatin plus the PI3K inhibitor (wortmannin), and sham-operated plus wortmannin. Simvastatin was administered intraperitoneally 30 minutes after SAH created by the standard endovascular perforation model. Histological parameters of the ipsilateral internal carotid artery (ICA-diameter, perimeter, and wall thickness) and neurological score were assessed at 24 hours.
FINDINGS
Mortality was reduced to zero in both the treated groups as compared to 20% in the vehicle-treated and 36% in the simvastatin plus wortmannin-treated groups. The decrease in ICA diameter and perimeter observed in vehicle-treated group (203.2 +/- 10.3 microm, 652.7 +/- 29.0 microm) as compared to sham (259.7 +/- 10.6, 865.4 +/- 39.5) were significantly attenuated by high-dose simvastatin (267.4 +/- 8.0, 882.4 +/- 30.0). The increase in wall thickness (vehicle 29.50 +/- 2.42 microm v/s sham 9.52 +/- 0.56 microm) was significantly attenuated by both high and low dose simvastatin (11.87 +/- 1.56, 19.75 +/- 1.40). These effects of simvastatin were blocked with the addition of wortmannin (162.7 +/- 20.6, 528.9 +/- 65.9, 29.19 +/- 1.97). High dose simvastatin improved the neurological deficits after SAH, but this was also blocked by wortmannin.
CONCLUSIONS
The beneficial effects of high dose simvastatin in ameliorating cerebral vasospasm are likely mediated by upregulation of the PI3K/Akt pathway.
影响因子：
8.3
作者：
GARCIA, JH;WAGNER, S;HU, XJ
通讯作者：
HU, XJ