PMID- 24126417
OWN - NLM
STAT- MEDLINE
DCOM- 20140210
LR  - 20211021
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 273
IP  - 3
DP  - 2013 Dec 15
TI  - Carbamazepine suppresses calpain-mediated autophagy impairment after 
      ischemia/reperfusion in mouse livers.
PG  - 600-10
LID - S0041-008X(13)00437-7 [pii]
LID - 10.1016/j.taap.2013.10.006 [doi]
AB  - 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 muM 
      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.
CI  - (c) 2013.
FAU - Kim, Jae-Sung
AU  - Kim JS
AD  - Department of Surgery, University of Florida, Gainesville, FL 32610, USA. 
      Electronic address: Jae.Kim@surgery.ufl.edu.
FAU - Wang, Jin-Hee
AU  - Wang JH
FAU - Biel, Thomas G
AU  - Biel TG
FAU - Kim, Do-Sung
AU  - Kim DS
FAU - Flores-Toro, Joseph A
AU  - Flores-Toro JA
FAU - Vijayvargiya, Richa
AU  - Vijayvargiya R
FAU - Zendejas, Ivan
AU  - Zendejas I
FAU - Behrns, Kevin E
AU  - Behrns KE
LA  - eng
GR  - R01 DK090115/DK/NIDDK NIH HHS/United States
GR  - AG028740/AG/NIA NIH HHS/United States
GR  - P30 AG028740/AG/NIA NIH HHS/United States
GR  - DK079879/DK/NIDDK NIH HHS/United States
GR  - R01 DK079879/DK/NIDDK NIH HHS/United States
GR  - DK090115/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20131012
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Anticonvulsants)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Atg7 protein, mouse)
RN  - 0 (Beclin-1)
RN  - 0 (Becn1 protein, mouse)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 33CM23913M (Carbamazepine)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 6.2.1.45 (Autophagy-Related Protein 7)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Anticonvulsants/pharmacology
MH  - Apoptosis Regulatory Proteins/genetics/metabolism
MH  - Autophagy/*drug effects
MH  - Autophagy-Related Protein 7
MH  - Beclin-1
MH  - Calcium/metabolism
MH  - Calpain/*adverse effects
MH  - Carbamazepine/*pharmacology
MH  - Hepatocytes/drug effects/metabolism
MH  - Liver/*drug effects/metabolism
MH  - Lysosomes/metabolism
MH  - Male
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microscopy, Confocal
MH  - Microtubule-Associated Proteins/genetics/metabolism
MH  - Mitochondria/metabolism
MH  - Reperfusion Injury/drug therapy
PMC - PMC3867813
MID - NIHMS532009
OTO - NOTNLM
OT  - Atg
OT  - Autophagy
OT  - CBZ
OT  - CQ
OT  - Calcium
OT  - FDA
OT  - Food & Drug Administration
OT  - Hepatocytes
OT  - I/R
OT  - IP(3)
OT  - Ischemia/reperfusion
OT  - KRH
OT  - Krebs-Ringer-N-2 hydroxyethylpiperazine-N-2 ethanesulfonic acid
OT  - LC3
OT  - MPT
OT  - Mitochondria
OT  - Mitochondrial permeability transition
OT  - PI
OT  - TMRM
OT  - autophagy-related proteins
OT  - carbamazepine
OT  - chloroquine
OT  - inositol-1,4,5-triphosphate
OT  - ischemia/reperfusion
OT  - microtubule-associated protein 1 light chain 3
OT  - mitochondrial permeability transition
OT  - propidium iodide
OT  - tetramethylrhodamine methylester
COIS- Conflict of interest The authors declare that there are no conflicts of interest.
EDAT- 2013/10/16 06:00
MHDA- 2014/02/11 06:00
PMCR- 2014/12/15
CRDT- 2013/10/16 06:00
PHST- 2013/07/26 00:00 [received]
PHST- 2013/09/29 00:00 [revised]
PHST- 2013/10/02 00:00 [accepted]
PHST- 2013/10/16 06:00 [entrez]
PHST- 2013/10/16 06:00 [pubmed]
PHST- 2014/02/11 06:00 [medline]
PHST- 2014/12/15 00:00 [pmc-release]
AID - S0041-008X(13)00437-7 [pii]
AID - 10.1016/j.taap.2013.10.006 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2013 Dec 15;273(3):600-10. doi: 
      10.1016/j.taap.2013.10.006. Epub 2013 Oct 12.