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

  • Transl Stroke Res. 2018 Aug;9(4):382-392. doi: 10.1007/s12975-017-0581-z.
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  5  6 ,  Jun Peng  7  8
Affiliations
  • 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.
  • 5. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. [email protected].
  • 6. Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, 410013, China. [email protected].
  • 7. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. [email protected].
  • 8. Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. [email protected].
PMID: 29103102 DOI: 10.1007/s12975-017-0581-z
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
Apoptosis; Brain; Emricasan; Ischemia/reperfusion; Necroptosis; Ponatinib.
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