Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simulta
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ORIGINAL ARTICLE
Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis Jing Tian 1,2 & Shu Guo 1 & Heng Chen 1 & Jing-Jie Peng 1,2 & Miao-Miao Jia 1 & Nian-Sheng Li 1,3 & Xiao-Jie Zhang 1,3 & Jie Yang 4 & Xiu-Ju Luo 1,2 & Jun Peng 1,3
Received: 25 August 2017 / Revised: 20 October 2017 / Accepted: 26 October 2017 # Springer Science+Business Media, LLC 2017
Abstract 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-
* Xiu-Ju Luo [email protected] * Jun Peng [email protected] 1
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
2
Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha 410013, China
3
Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
4
Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
treated brain but not the protein levels of necroptosis-relevant proteins: RIPK1, RIPK3, and mixed lineage kinase domainlike (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. Keywords Emricasan . Ponatinib . Ischemia/reperfusion . Apoptosis . Necroptosis . Brain
Introduction Ischemic stroke is a common disease with great danger for human health, accounting for 70–80% of cerebrova
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