Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
Nat Neurosci. 2012 Feb 26;15(4):574-80. doi: 10.1038/nn.3054.
Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x(L) is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ΔN-Bcl-x(L). We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-x(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-x(L), we generated knock-in mice expressing a caspase-resistant form of Bcl-x(L). The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-x(L) could be a potentially important therapeutic target in ischemic brain injury.
大鼠短暂性全脑缺血诱导海马 CA1 神经元迟发性死亡。早期事件包括半胱天冬酶激活、抗死亡 Bcl-2 家族蛋白的裂解和线粒体大通道活性。然而，这些事件是否在缺血诱导的神经元死亡中起因果作用尚不清楚。我们发现，Bcl-2 和 Bcl-x(L)抑制剂 ABT-737 增强肿瘤细胞死亡，可在临床相关的脑缺血模型中保护大鼠免受神经元死亡。Bcl-x(L)在成年神经元中表达明显，可被半胱天冬酶切割产生促死亡片段ΔN-Bcl-x(L)。我们发现，缺血前或缺血后给予 ABT-737 可抑制ΔN-Bcl-x(L)诱导的线粒体通道活性和神经元死亡。为了确定ΔN-Bcl-x(L)的因果关系，我们生成了表达 caspase 抗性 Bcl-x(L)形式的基因敲入小鼠。该基因敲入小鼠表现出明显降低的线粒体通道活性和降低的对缺血诱导的神经元死亡的易感性。这些发现表明，截短的 Bcl-x(L)可能是缺血性脑损伤的一个潜在重要治疗靶点。
