PMID- 26091107
OWN - NLM
STAT- MEDLINE
DCOM- 20160504
LR  - 20181203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 6
DP  - 2015
TI  - In Vitro Induction of Endothelial Apoptosis of the Post-Hypoxic Blood-Brain 
      Barrier by Isoflurane but Not by Sevoflurane and Midazolam.
PG  - e0130408
LID - 10.1371/journal.pone.0130408 [doi]
LID - e0130408
AB  - BACKGROUND: The effects of anesthetics on the injured brain continue to be the 
      subject of controversial discussion. Since isoflurane has recently been shown to 
      induce apoptosis of cerebral endothelial cells, this study compared different 
      anesthetic compounds regarding their potential to induce cerebro-vascular 
      apoptosis. METHODS: The in vitro model of the blood-brain barrier used in this 
      study consisted of astrocyte-conditioned human umbilical vein endothelial cells 
      (AC-HUVEC) has been used. After 24 h of deep hypoxia and reoxygenation or control 
      treatment, AC-HUVEC were exposed to 0, 0.5, 1.0, or 2.0 times the minimum 
      alveolar concentration of isoflurane or sevoflurane, or 0, 75, 150, or 300 nM of 
      midazolam for 2 h. After 24 h, AC-HUVEC were harvested, and the degree of 
      apoptosis was assessed by means of Western blots for the Bax and Bcl-2 ratio and, 
      for controls and the highest concentration groups, terminal 
      deoxynucleotidyl-mediated dUTP-biotin nick end labeling (TUNEL). RESULTS: Without 
      hypoxic pretreatment, 2.0 MAC of isoflurane slightly increased TUNEL intensity 
      compared to control and sevoflurane, but without any significant changes in the 
      Bax and Bcl-2 ratio. After hypoxic pretreatment, exposure to isoflurane led to a 
      multifold increase in the Bax and Bcl-2 ratio in a dose dependent manner, which 
      was also significantly higher than the ratio observed in the 2 MAC sevoflurane 
      group. TUNEL intensity in the post-hypoxic 2 MAC isoflurane group was increased 
      by a factor of 11 vs. control and by 40 vs. sevoflurane. Sevoflurane and 
      midazolam did not significantly alter these markers of apoptosis, when compared 
      to the control group. CONCLUSIONS: Isoflurane administered after hypoxia elevates 
      markers of apoptosis in endothelial cells transdifferentiated to the 
      cerebro-vascular endothelium. Endothelial apoptosis may be a previously 
      underestimated mechanism of anesthetic neurotoxicity. Administration of high 
      concentrations of isoflurane in experimental settings may have negative effects 
      on the blood-brain barrier.
FAU - Dittmar, Michael S
AU  - Dittmar MS
AD  - Department of Anesthesiology, Regensburg University Medical Center, Regensburg, 
      Germany.
FAU - Petermichl, Walter
AU  - Petermichl W
AD  - Department of Anesthesiology, Regensburg University Medical Center, Regensburg, 
      Germany.
FAU - Lindner, Regina
AU  - Lindner R
AD  - Department of Anesthesiology, Regensburg University Medical Center, Regensburg, 
      Germany.
FAU - Sinner, Barbara
AU  - Sinner B
AD  - Department of Anesthesiology, Regensburg University Medical Center, Regensburg, 
      Germany.
FAU - Graf, Bernhard M
AU  - Graf BM
AD  - Department of Anesthesiology, Regensburg University Medical Center, Regensburg, 
      Germany.
FAU - Schlachetzki, Felix
AU  - Schlachetzki F
AD  - Department of Neurology, Bezirksklinikum Regensburg, University of Regensburg, 
      Regensburg, Germany.
FAU - Gruber, Michael
AU  - Gruber M
AD  - Department of Anesthesiology, Regensburg University Medical Center, Regensburg, 
      Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150619
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Methyl Ethers)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (bcl-2-Associated X Protein)
RN  - 38LVP0K73A (Sevoflurane)
RN  - CYS9AKD70P (Isoflurane)
RN  - R60L0SM5BC (Midazolam)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Blood-Brain Barrier/metabolism
MH  - Cell Hypoxia
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Isoflurane/*pharmacology
MH  - Methyl Ethers/*pharmacology
MH  - Midazolam/*pharmacology
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Sevoflurane
MH  - bcl-2-Associated X Protein/metabolism
PMC - PMC4475016
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/06/20 06:00
MHDA- 2016/05/05 06:00
PMCR- 2015/06/19
CRDT- 2015/06/20 06:00
PHST- 2015/03/10 00:00 [received]
PHST- 2015/05/20 00:00 [accepted]
PHST- 2015/06/20 06:00 [entrez]
PHST- 2015/06/20 06:00 [pubmed]
PHST- 2016/05/05 06:00 [medline]
PHST- 2015/06/19 00:00 [pmc-release]
AID - PONE-D-15-10295 [pii]
AID - 10.1371/journal.pone.0130408 [doi]
PST - epublish
SO  - PLoS One. 2015 Jun 19;10(6):e0130408. doi: 10.1371/journal.pone.0130408. 
      eCollection 2015.