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

被引：14

作者：

Chen, Jui-Tai ^{[1
,2
]}

Lin, Yi-Ling ^{[3
]}

Chen, Ta-Liang ^{[4
]}

Tai, Yu-Ting ^{[2
]}

Chen, Cheng-Yu ^{[1
]}

Chen, Ruei-Ming ^{[3
,4
,5
,6
]}

机构：

[1] Taipei Med Univ, Grad Inst Clin Med, Coll Med, Taipei, Taiwan

[2] Taipei Med Univ, Wan Fang Hosp, Dept Anesthesiol, Taipei, Taiwan

[3] Taipei Med Univ, Wan Fang Hosp, Brain Dis Res Ctr, Taipei, Taiwan

[4] Taipei Med Univ, Taipei Med Univ Hosp, Anesthet Toxicol Res Ctr, Taipei, Taiwan

[5] Taipei Med Univ, Grad Inst Med Sci, Coll Med, 250 Wu Hsing St, Taipei 110, Taiwan

[6] Taipei Med Univ, Ctr Comprehens Canc, Taipei, Taiwan

来源：

TOXICOLOGY | 2016年 / 368卷

关键词：

Ketamine; Blood-brain barrier (BBB); Bradykinin; Calcium influx; Cerebrovascular endothelial cells; Occludin tight junction; BLOOD-BRAIN-BARRIER; INTRACELLULAR CALCIUM; APOPTOTIC INSULTS; EXPRESSION; RECEPTORS; DYNAMICS; PERMEABILITY; CLAUDIN-5; ROLES; MODEL;

D O I：

10.1016/j.tox.2016.09.004

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

引用

页码：142 / 151

页数：10

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