Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers

Jae Sung Kim, Jin Hee Wang, Thomas G. Biel, Do Sung Kim, Joseph A. Flores-Toro, Richa Vijayvargiya, Ivan Zendejas, Kevin E. Behrns

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Onset of the mitochondrial permeability transition (MPT) plays a causative role in ischemia/reperfusion (I/R) injury. Current therapeutic strategies for reducing reperfusion injury remain disappointing. Autophagy is a lysosome-mediated, catabolic process that timely eliminates abnormal or damaged cellular constituents and organelles such as dysfunctional mitochondria. I/R induces calcium overloading and calpain activation, leading to degradation of key autophagy-related proteins (Atg). Carbamazepine (CBZ), an FDA-approved anticonvulsant drug, has recently been reported to increase autophagy. We investigated the effects of CBZ on hepatic I/R injury. Hepatocytes and livers from male C57BL/6 mice were subjected to simulated in vitro, as well as in vivo I/R, respectively. Cell death, intracellular calcium, calpain activity, changes in autophagy-related proteins (Atg), autophagic flux, MPT and mitochondrial membrane potential after I/R were analyzed in the presence and absence of 20. μM CBZ. CBZ significantly increased hepatocyte viability after reperfusion. Confocal microscopy revealed that CBZ prevented calcium overloading, the onset of the MPT and mitochondrial depolarization. Immunoblotting and fluorometric analysis showed that CBZ blocked calpain activation, depletion of Atg7 and Beclin-1 and loss of autophagic flux after reperfusion. Intravital multiphoton imaging of anesthetized mice demonstrated that CBZ substantially reversed autophagic defects and mitochondrial dysfunction after I/R in vivo. In conclusion, CBZ prevents calcium overloading and calpain activation, which, in turn, suppresses Atg7 and Beclin-1 depletion, defective autophagy, onset of the MPT and cell death after I/R.

Original languageEnglish
Pages (from-to)600-610
Number of pages11
JournalToxicology and Applied Pharmacology
Volume273
Issue number3
DOIs
StatePublished - Dec 15 2013
Externally publishedYes

Keywords

  • Autophagy
  • Calcium
  • Hepatocytes
  • Ischemia/reperfusion
  • Mitochondria
  • Mitochondrial permeability transition

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    Kim, J. S., Wang, J. H., Biel, T. G., Kim, D. S., Flores-Toro, J. A., Vijayvargiya, R., Zendejas, I., & Behrns, K. E. (2013). Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers. Toxicology and Applied Pharmacology, 273(3), 600-610. https://doi.org/10.1016/j.taap.2013.10.006