p53 Potentiates Hippocampal Neuronal Death Caused by Global Ischemia
p53 Potentiates Hippocampal Neuronal Death Caused by Global Ischemia
复制标题
DOI：
10.1038/sj.jcbfm.9600293
复制
发表时间：
2006-03
影响因子：
6.3
通讯作者：
I. Yonekura;K. Takai;A. Asai;N. Kawahara;T. Kirino
中科院分区：
文献类型：
--
作者：
I. Yonekura;K. Takai;A. Asai;N. Kawahara;T. Kirino
虽然p53在各种应激后控制细胞死亡，但其在脑缺血后神经元死亡中的作用知之甚少。为了解决这个问题，我们通过三血管闭塞法使p53缺陷型（p53−/−和p53 +/−）小鼠（与C57 BL/6小鼠回交12代）和野生型小鼠（p53+/+）短暂性全脑缺血。尽管缺氧去极化和皮质血流量显示缺血的严重程度相似，但p53 +/+小鼠海马氨角（CA）1区的神经元死亡比p53 −/−小鼠广泛得多（存活神经元计数分别为9.3% ± 3.0%和非缺血性p53+/+对照组的61.3% ± 34.0%，P< 0.0037）。在p53 +/−小鼠中，也观察到类似的趋势，尽管没有统计学显著性（非缺血p53 +/+对照的43.5%）。在p53 +/+小鼠中，缺血后12 h海马CA 1区神经元中的p53样免疫反应增强，p53的直接下游靶蛋白Bax的信使核糖核酸也增加。这些结果表明，p53增强了体内缺血性神经元死亡，并提示该分子可能是脑缺血后神经元死亡的治疗靶点。
Although p53 controls cell death after various stresses, its role in neuronal death after brain ischemia is poorly understood. To address this issue, we subjectedp53-deficient (p53−/−andp53+/−) mice (backcrossed for 12 generations with C57BL/6 mice) and wild-type mice (p53+/+) to transient global ischemia by the three-vessel occlusion method. Despite similar severity of ischemia, as shown by anoxic depolarization and cortical blood flow, neuronal death in the hippocampal cornus ammonis (CA)1 region was much more extensive inp53+/+than inp53−/−mice (surviving neuronal count, 9.3% ± 3.0% versus 61.3% ± 34.0% of nonischemic p53+/+controls, respectively,P< 0.0037). Inp53+/−mice, a similar trend was also observed, though not statistically significant (43.5% of nonischemicp53+/+controls). Inp53+/+mice, p53-like immunoreactivity in hippocampal CA1 neurons was enhanced at 12 h after ischemia, and messenger ribonucleic acid for Bax, a direct downstream target of p53, was also increased. These results indicate that p53 potentiates ischemic neuronal deathin vivoand suggest that this molecule could be a therapeutic target in neuronal death after cerebral ischemia.