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Translational Stroke Research

, Volume 9, Issue 4, pp 382–392 | Cite as

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

  • Jing Tian
  • Shu Guo
  • Heng Chen
  • Jing-Jie Peng
  • Miao-Miao Jia
  • Nian-Sheng Li
  • Xiao-Jie Zhang
  • Jie Yang
  • Xiu-Ju Luo
  • Jun Peng
Original Article

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 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.

Keywords

Emricasan Ponatinib Ischemia/reperfusion Apoptosis Necroptosis Brain 

Notes

Funding Information

This work was supported by the National Natural Science Foundation of China, China (No. 81573430 to Xiu-Ju Luo; No. 81373409 to Jun Peng) and the Natural Science Foundation of Hunan Province, China (No. 2015JJ2156 to Xiu-Ju Luo).

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • 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
  1. 1.Department of Pharmacology, Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaChina
  2. 2.Department of Laboratory Medicine, Xiangya School of MedicineCentral South UniversityChangshaChina
  3. 3.Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaChina
  4. 4.Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina

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