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

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.

• Authors: 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
• Journal: Translational stroke research (Transl Stroke Res) Vol. 9 Issue 4 Pg. 382-392 (08 2018) ISSN: 1868-601X [Electronic] United States
• PMID: 29103102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
• Imidazoles
• Neuroprotective Agents
• Pentanoic Acids
• Pyridazines
• ponatinib
• Receptor-Interacting Protein Serine-Threonine Kinases
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Brain (drug effects)
• Caspases (metabolism)
• Disease Models, Animal
• Drug Synergism
• Drug Therapy, Combination
• Gene Expression Regulation (drug effects)
• Imidazoles (therapeutic use)
• Male
• Necrosis (prevention & control)
• Neurologic Examination
• Neuroprotective Agents (therapeutic use)
• Pentanoic Acids (therapeutic use)
• Pyridazines (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
• Reperfusion Injury (drug therapy)
• Statistics, Nonparametric