PMID- 24743508
OWN - NLM
STAT- MEDLINE
DCOM- 20150115
LR  - 20220408
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 4
DP  - 2014
TI  - Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving 
      PI3K/Akt pathway in the hippocampus of neonatal rats.
PG  - e93639
LID - 10.1371/journal.pone.0093639 [doi]
LID - e93639
AB  - Prolonged exposure to volatile anesthetics, such as isoflurane and sevoflurane, 
      causes neurodegeneration in the developing animal brains. Recent studies showed 
      that dexmedetomidine, a selective alpha2-adrenergic agonist, reduced 
      isoflurane-induced cognitive impairment and neuroapoptosis. However, the 
      mechanisms for the effect are not completely clear. Thus, we investigated whether 
      exposure to isoflurane or sevoflurane at an equivalent dose for anesthesia during 
      brain development causes different degrees of neuroapoptosis and whether this 
      neuroapoptosis is reduced by dexmedetomidine via effects on PI3K/Akt pathway that 
      can regulate cell survival. Seven-day-old (P7) neonatal Sprague-Dawley rats were 
      randomly exposed to 0.75% isoflurane, 1.2% sevoflurane or air for 6 h. Activated 
      caspase-3 was detected by immunohistochemistry and Western blotting. Phospho-Akt, 
      phospho-Bad, Akt, Bad and Bcl-xL proteins were detected by Western blotting in 
      the hippocampus at the end of exposure. Also, P7 rats were pretreated with 
      various concentrations of dexmedetomidine alone or together with PI3K inhibitor 
      LY294002, and then exposed to 0.75% isoflurane. Terminal deoxyribonucleotide 
      transferase-mediated dUTP nick end labeling (TUNEL) and activated caspase-3 were 
      used to detect neuronal apoptosis in their hippocampus. Isoflurane, not 
      sevoflurane at the equivalent dose, induced significant neuroapoptosis, decreased 
      the levels of phospho-Akt and phospho-Bad proteins, increased the expression of 
      Bad protein and reduced the ratio of Bcl-xL/Bad in the hippocampus. 
      Dexmedetomidine pretreatment dose-dependently inhibited isoflurane-induced 
      neuroapoptosis and restored protein expression of phospho-Akt and Bad as well as 
      the Bcl-xL/Bad ratio induced by isoflurane. Pretreatment with single dose of 75 
      microg/kg dexmedetomidine provided a protective effect similar to that with three 
      doses of 25 microg/kg dexmedetomidine. Moreover, LY294002, partly inhibited 
      neuroprotection of dexmedetomidine. Our results suggest that dexmedetomidine 
      pretreatment provides neuroprotection against isoflurane-induced neuroapoptosis 
      in the hippocampus of neonatal rats by preserving PI3K/Akt pathway activity.
FAU - Li, Yujuan
AU  - Li Y
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Zeng, Minting
AU  - Zeng M
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Chen, Weiqiang
AU  - Chen W
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, Guangdong, China; Department of Anesthesiology, Affiliated 
      Shantou Hospital of Sun Yat-sen University, Shantou, Guangdong, China.
FAU - Liu, Chuiliang
AU  - Liu C
AD  - Department of Anesthesiology, ChanCheng Center Hospital, Foshan, Guangdong, 
      China.
FAU - Wang, Fei
AU  - Wang F
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Han, Xue
AU  - Han X
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
FAU - Zuo, Zhiyi
AU  - Zuo Z
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, Guangdong, China; Department of Anesthesiology, University 
      of Virginia Health System, Charlottesville, Virginia, United States of America.
FAU - Peng, Shuling
AU  - Peng S
AD  - Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140417
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Anesthetics)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (bcl-Associated Death Protein)
RN  - 0 (bcl-X Protein)
RN  - 67VB76HONO (Dexmedetomidine)
RN  - CYS9AKD70P (Isoflurane)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Anesthetics/adverse effects
MH  - Animals
MH  - Animals, Newborn
MH  - Apoptosis/*drug effects
MH  - Dexmedetomidine/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Hippocampus/*cytology
MH  - Isoflurane/*adverse effects
MH  - Neuroprotective Agents/pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/*drug effects
MH  - bcl-Associated Death Protein/metabolism
MH  - bcl-X Protein/metabolism
PMC - PMC3990549
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/04/20 06:00
MHDA- 2015/01/16 06:00
PMCR- 2014/04/17
CRDT- 2014/04/19 06:00
PHST- 2014/01/19 00:00 [received]
PHST- 2014/03/04 00:00 [accepted]
PHST- 2014/04/19 06:00 [entrez]
PHST- 2014/04/20 06:00 [pubmed]
PHST- 2015/01/16 06:00 [medline]
PHST- 2014/04/17 00:00 [pmc-release]
AID - PONE-D-14-02782 [pii]
AID - 10.1371/journal.pone.0093639 [doi]
PST - epublish
SO  - PLoS One. 2014 Apr 17;9(4):e93639. doi: 10.1371/journal.pone.0093639. eCollection 
      2014.