Pifithrin-alpha reduces cerebral vasospasm by attenuating apoptosis of endothelial cells in a subarachnoid haemorrhage model of rat.
Pifithrin-alpha reduces cerebral vasospasm by attenuating apoptosis of endothelial cells in a subarachnoid haemorrhage model of rat.
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DOI：
10.1097/00029330-200803010-00009
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发表时间：
2008-03
影响因子：
6.1
通讯作者：
Junhao Yan;Xiao-mei Yang;Chunhua Chen;Qin Hu;J. Zhao;Xian-zhong Shi;Liju Luan;Lei Yang;Li-hua Qin;Chang‐man Zhou
中科院分区：
文献类型：
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作者：
Junhao Yan;Xiao-mei Yang;Chunhua Chen;Qin Hu;J. Zhao;Xian-zhong Shi;Liju Luan;Lei Yang;Li-hua Qin;Chang‐man Zhou
蛛网膜下腔出血（SAH）后脑血管痉挛的机制尚不清楚。在此，我们假设由p53及其靶基因emdash p53上调的凋亡调节因子（modulator of apoptosis，PD-A）诱导的内皮细胞凋亡在脑血管痉挛的发生中起重要作用。我们还观察了p53抑制剂pifithrin-alpha（PFT-α）降低p53和p53-A表达的作用，从而减少内皮细胞凋亡，减轻脑血管痉挛。方法雄性SD大鼠，体重300-350 g，随机分为5组：对照组（假手术）、SAH组、SAH+二甲基亚砜（DMSO）组、SAH + PFT-α（0.2 mg/kg）组和SAH + PFT-α（2.0 mg/kg）组。SAH后立即腹腔注射PFT-α。SAH后24小时处死大鼠。Western blot和免疫组化法检测p53、caspase-3、p54 A蛋白的表达。此外，还评估了各组的死亡率和神经系统评分。通过在单向ANOVA中进行方差分析，然后进行Tukey检验来确保统计学显著性。分别采用Dunn法和Fisher精确检验分析神经功能评分和死亡率评分。结果SAH后，基底动脉内皮细胞p53、caspase-3、TdT介导的dUTP缺口末端标记（TUNEL）阳性细胞数均明显增加（P<0.05），而PFT-α组明显减少（P <0.05）。结果表明，脑缺血后大鼠基底动脉内径增大，管壁厚度减小（P<0.05），死亡率和神经功能缺损程度降低（P<0.05）。结论PFT-α通过抑制p53诱导的脑血管内皮细胞凋亡，对脑血管痉挛的发生具有保护作用，可改善神经功能，降低死亡率。
BACKGROUND The mechanism of cerebral vasospasm following subarachnoid haemorrhage (SAH) is not understood. Here, we hypothesized that apoptosis of endothelial cells induced by p53 and its target gene em dash p53 upregulated modulator of apoptosis (PUMA) played an important role in development of cerebral vasospasm. We also observed the effects of a p53 inhibitor, pifithrin-alpha (PFT-alpha), on reducing the expression of p53 and PUMA, consequently decreasing the apoptosis of endothelial cells and alleviating cerebral vasospasm. METHODS Male Sprague-Dawley rats weighing 300-350 g were randomly divided into five groups: a control group (sham surgery), a SAH group, a SAH+dimethyl sulfoxide (DMSO) group, a SAH + PFT-alpha (0.2 mg/kg) group and a SAH + PFT-alpha (2.0 mg/kg) group. PFT-alpha was injected intraperitoneally immediately after SAH. Rats were sacrificed 24 hours after SAH. Western blot and immunohistochemical staining were used to detect the levels of p53, PUMA and caspase-3 protein. In addition, mortality and neurological scores were assessed for each group. Statistical significance was assured by analysis of variance performed in one way ANOVA followed by the Tukey test. The neurological and mortality scores were analyzed by Dunn's method and Fisher exact test, respectively. RESULTS After SAH, Western blot and immunohistochemical staining showed the levels of p53, PUMA and caspase-3 in the endothelial cells and the numbers of TdT mediated dUTP nick end labelling (TUNEL) positive endothelial cells were all significantly increased in the basilar arteries (P<0.05), but significantly reduced by PFT-alpha (P<0.05). These changes were accompanied by increasing diameters and declining wall thickness of basilar arteries (P<0.05), as well as reduced mortality and neurological deficits of the rats (P<0.05). CONCLUSIONS PFT-alpha could protect cerebral vessels from development of vasospasm and improve neurological outcome as well as reduce the mortality via suppressing apoptosis induced by p53 in the endothelial cells of cerebral vessels.