Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis

Translational Stroke Research
Jing TianJun Peng

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-treated brain but not the protein levels of necroptosis-relevant proteins: RIPK1, RIPK3, and mix...Continue Reading

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Citations

Mar 11, 2020·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Zhenhua ZhouJohn H Zhang
Jan 31, 2020·Oxidative Medicine and Cellular Longevity·Jing YuJohn H Zhang
May 6, 2019·Naunyn-Schmiedeberg's Archives of Pharmacology·Yi-Yue ZhangJun Peng
Oct 18, 2020·Archives of Biochemistry and Biophysics·Suchan LiaoSiriporn C Chattipakorn
Jan 11, 2020·Experimental Eye Research·Jing-Jie PengXiao-Bo Xia
Nov 3, 2020·Frontiers in Cellular Neuroscience·Jie LiuYi Yang
Jun 21, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Chengdi LiuGuanhua Du
Jul 15, 2021·Oxidative Medicine and Cellular Longevity·Yue ZhouJinwen Ge
Sep 9, 2021·Cardiovascular Drugs and Therapy·Yi-Yue ZhangJun Peng
Sep 18, 2020·Current Pharmaceutical Design·Lei HuangJohn H Zhang

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Methods Mentioned

BETA
protein assay

Software Mentioned

ARRIVE
Image J

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