Inhibition of receptor-interacting protein 3 upregulation and nuclear translocation involved in Necrostatin-1 protection against hippocampal neuronal programmed necrosis induced by ischemia/reperfusion injury
Inhibition of receptor-interacting protein 3 upregulation and nuclear translocation involved in Necrostatin-1 protection against hippocampal neuronal programmed necrosis induced by ischemia/reperfusion injury
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DOI：
10.1016/j.brainres.2015.03.024
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发表时间：
2015-06-03
期刊：
影响因子：
2.9
通讯作者：
Wang, Jing-ye
中科院分区：
文献类型：
--
作者：
Yin, Bo;Xu, Yang;Wang, Jing-ye
受体相互作用蛋白 3 (RIP3) 是肿瘤坏死因子诱导的坏死性凋亡中的关键分子开关，需要形成 RIP3 RIP1 复合物。我们最近发现，20 分钟全脑缺血/再灌注 (I/R) 损伤引起的海马 comu ammonis 1 (CA1) 神经元死亡是一种程序性坏死。然而，这一过程背后的机制仍不清楚，在此进行了研究。采用四支血管阻断法诱导全脑缺血，缺血前1 h脑室内注射坏死性凋亡特异性抑制剂Necrostatin-1（Nec-1）。正常情况下，在海马 CA1 神经元中，RIP1 和 RIP3 位于细胞质中。然而，I/R损伤后，RIP3上调并易位至细胞核，而RIP1不受影响。 Nec-1 预处理可防止海马 CA1 神经元死亡和 I/R 诱导的 RIP3 变化。 Nec-1 还可抑制 I/R 损伤后海马 NAD+ 水平的降低以及溶酶体中组织蛋白酶-B 的释放。我们的数据表明，Nec-1 通过阻止 RIP3 上调和核转位以及 NAD+ 消耗和组织蛋白酶 B 释放来抑制神经元死亡。 RIP3的核转位此前尚未报道，因此这可能是RIP3在缺血性损伤过程中的重要作用。 (C) 2015 Elsevier B.V. 保留所有权利。
Receptor-interacting protein 3 (RIP3) is a key molecular switch in tumor necrosis factor-induced necroptosis requiring the formation of an RIP3 RIP1 complex. We have recently shown that hippocampal comu ammonis 1 (CA1) neuronal death induced by 20-min global cerebral ischemia/reperfusion (I/R) injury is a form of programmed necrosis. However, the mechanism behind this process is still unclear and was studied here. Global cerebral ischemia was induced by the four-vessel occlusion method and Necrostatin-1 (Nec-1), a specific inhibitor of necroptosis, was administered by intracerebroventricular injection 1 h before ischemia. Normally, in the hippocampal CA1 neurons, RIP1 and RIP3 are located in the cytoplasm. However, after I/R injury, RIP3 was upregulated and translocated to the nucleus while RIP1 was not affected. Nec-1 pretreatment prevented hippocampal CA1 neuronal death and I/R induced changes in RIP3. Decreased level of NAD+ in hippocampus and the release of cathepsin-B from lysosomes after I/R injury were also inhibited by Nec-1. Our data demonstrate that Nec-1 inhibits neuronal death by preventing RIP3 upregulation and nuclear translocation, as well as NAD+ depletion and cathepsin-B release. The nuclear translocation of RIP3 has not been reported previously, so this may be an important role for RIP3 during ischemic injury. (C) 2015 Elsevier B.V. All rights reserved.