FOREBRAIN NEURONAL SPECIFIC ABLATION OF P53 GENE PROVIDES PROTECTION IN A CORTICAL ISCHEMIC STROKE MODEL
FOREBRAIN NEURONAL SPECIFIC ABLATION OF P53 GENE PROVIDES PROTECTION IN A CORTICAL ISCHEMIC STROKE MODEL
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DOI：
10.1016/j.neuroscience.2015.03.018
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发表时间：
2015-06-04
期刊：
影响因子：
3.3
通讯作者：
Luo, Y.
中科院分区：
文献类型：
--
作者：
Filichia, E.;Shen, H.;Luo, Y.
脑缺血性损伤涉及缺血部位多种细胞类型的死亡。作为细胞死亡的关键调节因子，p53基因与中风中细胞损失的调节有关。在用p53抑制剂预处理的中风动物或传统的p53敲除（ko）小鼠中发现较少的局灶性损伤。然而，p53基因是否在调节神经元细胞死亡中起直接作用尚不清楚。在这项研究中，在全球抑制p53功能的药理学抑制剂和传统的p53 KO小鼠，我们利用神经元特异性条件KO小鼠系（CamcreTRP 53（loxP/loxP）），以实现前脑神经元特异性缺失的p53和检查缺血诱导的细胞死亡的神经元中的作用的p53基因。采用免疫组化方法检测脑卒中后p53的表达，并通过分析脑梗死面积和脑卒中引起的行为缺陷来评估脑卒中的预后。我们的数据表明，p53表达上调的缺血区域中的神经元细胞在野生型（wt）小鼠，但不是在CamcreTRP 53（loxP/loxP）ko小鼠。缺失前脑神经元中的p53基因导致ko小鼠的梗死面积减少。在自动活动室中测量的运动行为显示，在大脑中动脉闭塞（MCAo）后，与野生型小鼠相比，CamcreTRP 53 loxP/loxP ko小鼠具有较少的运动缺陷。我们的结论是，操纵p53在神经元中的表达可能会导致独特的治疗中风的发展。(C)2015年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Cerebral ischemic injury involves death of multiple cell types at the ischemic sites. As a key regulator of cell death, the p53 gene has been implicated in the regulation of cell loss in stroke. Less focal damage is found in stroke animals pre-treated with a p53 inhibitor or in traditional p53 knockout (ko) mice. However, whether the p53 gene plays a direct role in regulating neuronal cell death is unknown. In this study, in contrast to the global inhibition of p53 function by pharmacological inhibitors and in traditional p53 ko mice, we utilized a neuronal specific conditional ko mouse line (CamcreTRP53(loxP/loxP)) to achieve forebrain neuronal specific deletion of p53 and examined the role of the p53 gene in ischemia-induced cell death in neurons. Expression of p53 after stroke is examined using the immunohistochemical method and the outcome of stroke is examined by analysis of infarction size and behavioral deficits caused by stroke. Our data showed that p53 expression is upregulated in the ischemic region in neuronal cells in wildtype (wt) mice but not in CamcreTRP53(loxP/loxP) ko mice. Deletion of the p53 gene in forebrain neurons results in a decreased infarction area in ko mice. Locomotor behavior, measured in automated activity chambers, showed that CamcreTRP53 loxP/loxP ko mice have less locomotor deficits compared to wt mice after middle cerebral artery occlusion (MCAo). We conclude that manipulation of p53 expression in neurons may lead to unique therapeutic development in stroke. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.