Severe Global Cerebral Ischemia-Induced Programmed Necrosis of Hippocampal CA1 Neurons in Rat Is Prevented by 3-Methyladenine: A Widely Used Inhibitor of Autophagy
Severe Global Cerebral Ischemia-Induced Programmed Necrosis of Hippocampal CA1 Neurons in Rat Is Prevented by 3-Methyladenine: A Widely Used Inhibitor of Autophagy
复制标题
3-甲基腺嘌呤：一种广泛使用的自噬抑制剂，可以预防严重的全脑缺血引起的大鼠海马 CA1 神经元程序性坏死
DOI：
10.1097/nen.0b013e31821352bd
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发表时间：
2011-04-01
影响因子：
3.2
通讯作者：
Luo, Ben-Yan
中科院分区：
文献类型：
--
作者：
Wang, Jin-Ye;Xia, Qiang;Luo, Ben-Yan
全脑缺血/再灌注损伤诱导的迟发性神经元死亡的真正程序性机制尚未完全确定。自噬性细胞死亡和程序性坏死是区别于凋亡的两种程序性细胞死亡。在这里，我们研究了年轻成年大鼠20分钟严重的全脑缺血/再灌注损伤后海马角氨1神经元死亡的死亡机制，以及广泛使用的自噬抑制剂3-甲基腺嘌呤（3-MA）的影响。电镜观察到的形态学变化，以及自噬激活、转移酶介导的UTP缺口末端标记阳性神经元和迟发性死亡，表明在这种模式中诱导的角氨1神经元死亡是程序性坏死。Western blot和免疫组化均未检测到损伤后caspase-3的明显激活。3-MA治疗提供了时间依赖性的保护，对角氨1神经元死亡，在7天的再灌注时，它是在缺血前给药，再灌注后60分钟给药是没有好处的。缺血前给予3-MA可抑制损伤后溶酶体酶组织蛋白酶B的再分布，这可能是3-MA保护缺血性神经元损伤的另一重要机制。
The true programmed mechanisms of delayed neuronal death induced by global cerebral ischemia/reperfusion injury remain incompletely characterized. Autophagic cell death and programmed necrosis are 2 kinds of programmed cell death distinct from apoptosis. Here, we studied the death mechanisms of hippocampal cornu ammonis 1 neuronal death after a 20-minute severe global ischemia/reperfusion injury in young adult rats and the effects of 3-methyladenine (3-MA), a widely used inhibitor of autophagy. The morphological changes detected by electron microscopy, together with the activation of autophagy, transferase-mediated UTP nick end-labeling-positive neurons, and delayed death, demonstrated that cornu ammonis 1 neuronal death induced in this paradigm was programmed necrosis. No significant activation of caspase-3 after injury was detected by Western blot and immunohistochemistry. Treatment with 3-MA provided time-dependent protection against cornu ammonis 1 neuronal death at 7 days of reperfusion when it was administered before ischemia; administration 60 minutes after reperfusion was not beneficial. The redistribution of the lysosomal enzyme cathepsin B after injury was inhibited by 3-MA administered before ischemia, suggesting that this might be another important mechanism for the protective effect of 3-MA in ischemic neuronal injury.