Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis
Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis
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Emricasan 与 Ponatinib 组合通过同时预防细胞凋亡和坏死性凋亡协同减少大鼠脑缺血/再灌注损伤
DOI：
10.1007/s12975-017-0581-z
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发表时间：
2017-11
影响因子：
6.9
通讯作者：
Peng Jun
中科院分区：
文献类型：
--
作者：
Tian Jing;Guo Shu;Chen Heng;Peng Jing Jie;Jia Miao Miao;Li Nian Sheng;Zhang Xiao Jie;Yang Jie;Luo Xiu Ju;Peng Jun
细胞凋亡和受体相互作用蛋白激酶1/3（RIPK 1/3）介导的坏死性凋亡参与脑缺血/再灌注（I/R）损伤。Emricasan是肝病临床试验中的半胱天冬酶抑制剂，而Ponatinib可能是RIPK 1/3的潜在抑制剂。本研究旨在探讨恩利卡生和/或泊那替尼对脑I/R损伤的影响及其机制。首先，我们评估了在不同条件下的脑I/R模型中的细胞凋亡和坏死的状态，在缺血2小时和再灌注24小时的条件下，显示出明显的细胞凋亡和坏死;接下来，我们测试了emricasan或Ponatinib对脑I/R损伤的预防或治疗作用。在缺血前或缺血后给予emricasan或ponatinib可降低神经功能缺损评分和梗死体积;最后，检查emricasan与ponatinib对I/R损伤的联合治疗效果。与单用相比，恩利卡生和泊那替尼联合应用可进一步减少I/R损伤。Emricasan降低了I/R处理脑中半胱氨酸蛋白酶-8/-3的活性，但未降低坏死性凋亡相关蛋白：RIPK 1、RIPK 3和混合谱系激酶结构域样（MLKL）的蛋白水平，而Ponatinib抑制了这些蛋白的表达，但未抑制半胱氨酸蛋白酶-8/-3的活性。emricasan与泊那替尼联合可抑制半胱天冬酶-8/-3和坏死性凋亡相关蛋白。基于这些观察结果，我们得出结论，emricasan与泊那替尼的组合可以通过同时预防细胞凋亡和坏死性凋亡来协同减少大鼠脑中的I/R损伤。本研究结果为扩大恩利卡生和泊那替尼治疗缺血性脑卒中的临床适应证奠定了基础。
Apoptosis and receptor-interacting protein kinase 1/3(RIPK1/3)-mediated necroptosis contribute to the cerebral ischemia/reperfusion (I/R) injury. Emricasan is an inhibitor of caspases in clinical trials for liver diseases while ponatinib could be a potential inhibitor for RIPK1/3. This study aims to investigate the effect of emricasan and/or ponatinib on cerebral I/R injury and the underlying mechanisms. Firstly, we evaluated the status of apoptosis and necroposis in a rat model of cerebral I/R under different conditions, which showed noticeable apoptosis and necroptosis under condition of 2-h ischemia and 24-h reperfusion; next, the preventive or therapeutic effect of emricasan or ponatinib on cerebral I/R injury was tested. Administration of emricasan or ponatinib either before or after ischemia could decrease the neurological deficit score and infarct volume; finally, the combined therapeutic effect of emricasan with ponatinib on I/R injury was examined. Combined application of emricasan and ponatinib could further decrease the I/R injury compared to single application. Emricasan decreased the activities of capase-8/-3 in the I/R-treated brain but not the protein levels of necroptosis-relevant proteins: RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL), whereas ponatinib suppressed the expressions of these proteins but not the activities of capase-8/-3. Combination of emricasan with ponatinib could suppress both capase-8/-3 and necroptosis-relevant proteins. Based on these observations, we conclude that combination of emricasan with ponatinib could synergistically reduce I/R injury in rat brain through simultaneous prevention of apoptosis and necroptosis. Our findings might lay a basis on extension of the clinical indications for emricasan and ponatinib in treating ischemic stroke.
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神经退行性疾病中的坏死性凋亡：潜在的治疗靶点
影响因子：
9
作者：
Zhang S;Tang MB;Luo HY;Shi CH;Xu YM
通讯作者：
Xu YM
影响因子：
8.3
作者：
Zille M;Karuppagounder SS;Chen Y;Gough PJ;Bertin J;Finger J;Milner TA;Jonas EA;Ratan RR
通讯作者：
Ratan RR
影响因子：
4.4
作者：
Beisner, DR;Ch'en, IL;Hedrick, SM
通讯作者：
Hedrick, SM
影响因子：
8.3
作者：
Schäbitz, WR;Schade, H;Schwab, S
通讯作者：
Schwab, S
DOI：
10.1016/s0169-328x(01)00058-4
发表时间：
2001-04-18
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Harrison, DC;Davis, RP;Philpott, KL
通讯作者：
Philpott, KL