μ-Calpain activation, DNA fragmentation, and synergistic effects of caspase and calpain inhibitors in protecting hippocampal neurons from ischemic damage
μ-Calpain activation, DNA fragmentation, and synergistic effects of caspase and calpain inhibitors in protecting hippocampal neurons from ischemic damage
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DOI：
10.1016/s0006-8993(00)02301-5
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发表时间：
2000-06-02
期刊：
影响因子：
2.9
通讯作者：
Winckler, J
中科院分区：
文献类型：
--
作者：
Rami, A;Agarwal, R;Winckler, J
分化的细胞似乎分享了通过激活内部编码的自杀程序来诱导自己死亡的能力。当被激活时，这个自杀程序会启动一种典型的细胞死亡形式，称为细胞凋亡。细胞凋亡研究中的一个中心挑战是了解启动和影响细胞凋亡级联反应的机制。我们测试了calain在缺血条件下细胞程序性死亡中的潜在作用，发现calain在形态变化、DNA断裂和死亡之前被激活，(2)calain在DNA阶梯之前被移位到细胞核，(3)caspase抑制剂和/或calain抑制剂的预处理不仅以协同方式阻止了酶的蛋白分解作用，而且还以协同方式阻止了CA1亚区细胞的死亡过程。综上所述，本研究结果进一步证明了蛋白水解酶可能在细胞凋亡中发挥作用，并将其扩展到内源性蛋白水解酶能够诱导显著的DNA片段化和染色质凝聚的可能性，这是目前用于定义凋亡性死亡的主要标准。此外，caspase和calain抑制剂在保护神经元免受缺血性损伤方面的协同作用表明，caspase和calain在细胞凋亡过程中存在串扰。(C)2000 Elsevier Science B.V.保留所有权利。
The differentiated cells seem to share the ability to induce their own death by the activation of an internally encoded suicide program. When activated, this suicide program initiates a characteristic form of cell death called apoptosis. A central challenge in apoptosis research is understanding the mechanisms by which apoptotic cascades are initiated and affected. We tested a potential role for calpain in the programmed cell death under ischemic conditions and found that calpain is (1) activated at a time preceding morphological changes, DNA fragmentation and death, (2) that calpain is translocated to the nucleus before DNA laddering, (3) pretreatment with caspase inhibitors and/or calpain inhibitors block not only the proteolytic actions of the enzyme, but also the cell death process itself in the CA1 subfield after transient global ischemia in a synergistic manner. In conclusion, the present results contribute additional evidence that proteases may play a functional role in apoptotic cell death and extend them to include the possibility that endogenous proteases are capable of inducing the striking DNA fragmentation and chromatin condensation, which are the principle criteria currently used to define apoptotic death. Moreover, the synergistic effect of caspase and calpain inhibitors in protecting neurons form ischemic damage suggests that then is a cross-talk between caspase and calpain during apoptosis. (C) 2000 Elsevier Science B.V. All rights reserved.