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.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Anesthesiology, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jui-Tai
authors.initials: JT
authors.lastname: Chen
authors.affiliation: Brain Disease Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Anesthetics Toxicology Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ta-Liang
authors.initials: TL
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Brain Disease Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan; Anesthetics Toxicology Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan. Electronic address: rmchen@tmu.edu.tw.
authors.forename: Ruei-Ming
authors.initials: RM
authors.lastname: Chen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001920:Bradykinin / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D016638:Critical Illness / Q000628:therapy; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D062793:Occludin / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects*
chemical_list: D062793:Occludin; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D007649:Ketamine; D001920:Bradykinin; D002118:Calcium
keywords: Blood-brain barrier (BBB); Bradykinin; Calcium influx; Cerebrovascular endothelial cells; Ketamine; Occludin tight junction