Abstract

Following brain injury, a sequence of mechanisms leads to disruption of the blood-brain barrier (BBB) and subsequent cerebral edema, which is thought to begin with activation of bradykinin. Our previous studies showed that ketamine, a widely used intravenous anesthetic agent, can suppress bradykinin-induced cell dysfunction. This study further aimed to evaluate the protective effects of ketamine against bradykinin-induced disruption of the mouse cerebrovascular endothelial cell (MCEC)-constructed tight junction barrier and the possible mechanisms. Exposure of MCECs to bradykinin increased intracellular calcium (Ca2+) concentrations in a time-dependent manner. However, pretreatment of MCECs with ketamine time- and concentration-dependently lowered the bradykinin-induced calcium influx. As to the mechanisms, although exposure of MCECs to ketamine induced bradykinin R1 receptor protein and mRNA expression, this anesthetic did not change levels of the bradykinin R2 receptor, a major receptor that responds to bradykinin stimulation. Bradykinin increased amounts of soluble occludin in MCECs, but pretreatment with ketamine alleviated this disturbance in occludin polymerization. Consequently, exposure to bradykinin decreased the transendothelial electronic resistance in the MCEC-constructed tight junction barrier. However, pretreatment with ketamine attenuated the bradykinin-induced disruption of the tight junction barrier. Taken together, this study shows that ketamine at a therapeutic concentration can protect against bradykinin-induced breakage of the BBB via suppressing calcium-dependent redistribution of occludin tight junctions. Thus, ketamine has the potential for maintaining the BBB in critically ill patients with severe brain disorders.

Original languageEnglish
Pages (from-to)142-151
Number of pages10
JournalToxicology
Volume368-369
DOIs
Publication statusPublished - Aug 10 2016

Fingerprint

Occludin
Tight Junctions
Endothelial cells
Ketamine
Bradykinin
Polymerization
Endothelial Cells
Calcium
Blood-Brain Barrier
Bradykinin Receptors
Anesthetics
Brain
Intravenous Anesthetics
Brain Edema
Brain Diseases
Critical Illness
Brain Injuries

Keywords

  • Blood-brain barrier (BBB)
  • Bradykinin
  • Calcium influx
  • Cerebrovascular endothelial cells
  • Ketamine
  • Occludin tight junction

ASJC Scopus subject areas

  • Toxicology

Cite this

@article{30c789e1bf934afe99fedff19a950ac6,
title = "Ketamine alleviates bradykinin-induced disruption of the mouse cerebrovascular endothelial cell-constructed tight junction barrier via a calcium-mediated redistribution of occludin polymerization",
abstract = "Following brain injury, a sequence of mechanisms leads to disruption of the blood-brain barrier (BBB) and subsequent cerebral edema, which is thought to begin with activation of bradykinin. Our previous studies showed that ketamine, a widely used intravenous anesthetic agent, can suppress bradykinin-induced cell dysfunction. This study further aimed to evaluate the protective effects of ketamine against bradykinin-induced disruption of the mouse cerebrovascular endothelial cell (MCEC)-constructed tight junction barrier and the possible mechanisms. Exposure of MCECs to bradykinin increased intracellular calcium (Ca2+) concentrations in a time-dependent manner. However, pretreatment of MCECs with ketamine time- and concentration-dependently lowered the bradykinin-induced calcium influx. As to the mechanisms, although exposure of MCECs to ketamine induced bradykinin R1 receptor protein and mRNA expression, this anesthetic did not change levels of the bradykinin R2 receptor, a major receptor that responds to bradykinin stimulation. Bradykinin increased amounts of soluble occludin in MCECs, but pretreatment with ketamine alleviated this disturbance in occludin polymerization. Consequently, exposure to bradykinin decreased the transendothelial electronic resistance in the MCEC-constructed tight junction barrier. However, pretreatment with ketamine attenuated the bradykinin-induced disruption of the tight junction barrier. Taken together, this study shows that ketamine at a therapeutic concentration can protect against bradykinin-induced breakage of the BBB via suppressing calcium-dependent redistribution of occludin tight junctions. Thus, ketamine has the potential for maintaining the BBB in critically ill patients with severe brain disorders.",
keywords = "Blood-brain barrier (BBB), Bradykinin, Calcium influx, Cerebrovascular endothelial cells, Ketamine, Occludin tight junction",
author = "Chen, {Jui Tai} and Lin, {Yi Ling} and Chen, {Ta Liang} and Yu-Ting Tai and Chen, {Cheng Yu} and Chen, {Ruei Ming}",
year = "2016",
month = "8",
day = "10",
doi = "10.1016/j.tox.2016.09.004",
language = "English",
volume = "368-369",
pages = "142--151",
journal = "Toxicology",
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TY - JOUR

T1 - Ketamine alleviates bradykinin-induced disruption of the mouse cerebrovascular endothelial cell-constructed tight junction barrier via a calcium-mediated redistribution of occludin polymerization

AU - Chen, Jui Tai

AU - Lin, Yi Ling

AU - Chen, Ta Liang

AU - Tai, Yu-Ting

AU - Chen, Cheng Yu

AU - Chen, Ruei Ming

PY - 2016/8/10

Y1 - 2016/8/10

N2 - Following brain injury, a sequence of mechanisms leads to disruption of the blood-brain barrier (BBB) and subsequent cerebral edema, which is thought to begin with activation of bradykinin. Our previous studies showed that ketamine, a widely used intravenous anesthetic agent, can suppress bradykinin-induced cell dysfunction. This study further aimed to evaluate the protective effects of ketamine against bradykinin-induced disruption of the mouse cerebrovascular endothelial cell (MCEC)-constructed tight junction barrier and the possible mechanisms. Exposure of MCECs to bradykinin increased intracellular calcium (Ca2+) concentrations in a time-dependent manner. However, pretreatment of MCECs with ketamine time- and concentration-dependently lowered the bradykinin-induced calcium influx. As to the mechanisms, although exposure of MCECs to ketamine induced bradykinin R1 receptor protein and mRNA expression, this anesthetic did not change levels of the bradykinin R2 receptor, a major receptor that responds to bradykinin stimulation. Bradykinin increased amounts of soluble occludin in MCECs, but pretreatment with ketamine alleviated this disturbance in occludin polymerization. Consequently, exposure to bradykinin decreased the transendothelial electronic resistance in the MCEC-constructed tight junction barrier. However, pretreatment with ketamine attenuated the bradykinin-induced disruption of the tight junction barrier. Taken together, this study shows that ketamine at a therapeutic concentration can protect against bradykinin-induced breakage of the BBB via suppressing calcium-dependent redistribution of occludin tight junctions. Thus, ketamine has the potential for maintaining the BBB in critically ill patients with severe brain disorders.

AB - Following brain injury, a sequence of mechanisms leads to disruption of the blood-brain barrier (BBB) and subsequent cerebral edema, which is thought to begin with activation of bradykinin. Our previous studies showed that ketamine, a widely used intravenous anesthetic agent, can suppress bradykinin-induced cell dysfunction. This study further aimed to evaluate the protective effects of ketamine against bradykinin-induced disruption of the mouse cerebrovascular endothelial cell (MCEC)-constructed tight junction barrier and the possible mechanisms. Exposure of MCECs to bradykinin increased intracellular calcium (Ca2+) concentrations in a time-dependent manner. However, pretreatment of MCECs with ketamine time- and concentration-dependently lowered the bradykinin-induced calcium influx. As to the mechanisms, although exposure of MCECs to ketamine induced bradykinin R1 receptor protein and mRNA expression, this anesthetic did not change levels of the bradykinin R2 receptor, a major receptor that responds to bradykinin stimulation. Bradykinin increased amounts of soluble occludin in MCECs, but pretreatment with ketamine alleviated this disturbance in occludin polymerization. Consequently, exposure to bradykinin decreased the transendothelial electronic resistance in the MCEC-constructed tight junction barrier. However, pretreatment with ketamine attenuated the bradykinin-induced disruption of the tight junction barrier. Taken together, this study shows that ketamine at a therapeutic concentration can protect against bradykinin-induced breakage of the BBB via suppressing calcium-dependent redistribution of occludin tight junctions. Thus, ketamine has the potential for maintaining the BBB in critically ill patients with severe brain disorders.

KW - Blood-brain barrier (BBB)

KW - Bradykinin

KW - Calcium influx

KW - Cerebrovascular endothelial cells

KW - Ketamine

KW - Occludin tight junction

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U2 - 10.1016/j.tox.2016.09.004

DO - 10.1016/j.tox.2016.09.004

M3 - Article

VL - 368-369

SP - 142

EP - 151

JO - Toxicology

JF - Toxicology

SN - 0300-483X

ER -