Effects of Volatile Anesthetics versus Ketamine on Blood-Brain Barrier Permeability via Lipid-Mediated Alterations of Endothelial Cell Membranes
Effects of Volatile Anesthetics versus Ketamine on Blood-Brain Barrier Permeability via Lipid-Mediated Alterations of Endothelial Cell Membranes
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DOI：
10.1124/jpet.122.001281
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发表时间：
2023-05-01
影响因子：
3.5
通讯作者：
Bickel, Ulrich
中科院分区：
文献类型：
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作者：
Noorani, Behnam;Chowdhury, Ekram Ahmed;Bickel, Ulrich
本研究的目的是研究临床相关浓度的挥发性麻醉药异氟醚和七氟醚对脂膜流动性和血脑屏障（BBB）通透性的影响。我们使用红细胞血影（荧光素钠渗透性）、脑微血管内皮细胞单层（[13 C]蔗糖和荧光素渗透性）或脂质体（荧光各向异性）分析了异氟烷或氯胺酮的体外作用。此外，我们确定了小鼠暴露于异氟烷30分钟对脑紧密连接蛋白的影响。最后，我们研究了在清醒状态下，在异氟烷、七氟烷或氯胺酮/甲苯噻嗪麻醉下，小鼠静脉给药后[13 C]甘露醇和[13 C]蔗糖的体内脑摄取。1 mM和5 mM浓度的异氟烷以浓度依赖性方式增加红细胞血影的荧光素流出。同样，在暴露于3%（v/v）异氟烷的内皮细胞单层中，荧光素的渗透系数增加约25%，[13 C]蔗糖的渗透系数增加约40%，而跨内皮阻力和细胞活力保持不受影响。尽管异氟烷导致脂质体各向异性值显著降低，但氯胺酮/甲苯噻嗪未显示任何影响。与氯胺酮/甲苯噻嗪麻醉或清醒状态相比，异氟烷或七氟烷麻醉下小鼠体内被动渗透性标志物的脑摄取清除率（表观Kin）约为氯胺酮/甲苯噻嗪麻醉或清醒状态下的两倍。小鼠体内暴露于异氟烷未改变任何脑紧密连接蛋白。我们的数据支持膜透化而不是细胞间紧密连接的松动是体内内皮细胞单层和BBB渗透性增加的潜在机制。意义声明血脑屏障控制内源性物质和外源性物质从循环进入中枢神经系统。挥发性麻醉剂（如异氟烷）改变细胞膜的脂质结构，短暂促进大脑吸收渗透性差的亲水性小分子。当潜在的神经毒性药物在吸入麻醉剂下获得对中枢神经系统的增强进入时，可能会产生临床意义。
The purpose of this study was to investigate the effects of the volatile anesthetic agents isoflurane and sevoflurane, at clini-cally relevant concentrations, on the fluidity of lipid membranes and permeability of the blood-brain barrier (BBB). We analyzed the in vitro effects of isoflurane or ketamine using erythrocyte ghosts (sodium fluorescein permeability), monolayers of brain microvascular endothelial cells ([13C]sucrose and fluorescein permeability), or liposomes (fluorescence anisotropy). Additionally, we determined the effects of 30-minute exposure of mice to iso-flurane on the brain tight junction proteins. Finally, we investigated in vivo brain uptake of [13C]mannitol and [13C]sucrose after intra-venous administration in mice under anesthesia with isoflurane, sevoflurane, or ketamine/xylazine in addition to the awake con-dition. Isoflurane at 1-mM and 5-mM concentrations increased fluorescein efflux from the erythrocyte ghosts in a concentration -dependent manner. Similarly, in endothelial cell monolayers ex-posed to 3% (v/v) isoflurane, permeability coefficients rose by about 25% for fluorescein and 40% for [13C]sucrose, whereas transendothelial resistance and cell viability remained unaffected. Although isoflurane caused a significant decrease in liposomes anisotropy values, ketamine/xylazine did not show any effects. Brain uptake clearance (apparent Kin) of the passive permeability markers in vivo in mice approximately doubled under isoflurane or sevoflurane anesthesia compared with either ketamine/xylazine anesthesia or the awake condition. In vivo exposure of mice to iso-flurane did not change any of the brain tight junction proteins. Our data support membrane permeabilization rather than loosening of intercellular tight junctions as an underlying mechanism for in-creased permeability of the endothelial cell monolayers and the BBB in vivo.SIGNIFICANCE STATEMENT The blood-brain barrier controls the entry of endogenous substan-ces and xenobiotics from the circulation into the central nervous system. Volatile anesthetic agents like isoflurane alter the lipid structure of cell membranes, transiently facilitating the brain up-take of otherwise poorly permeable, hydrophilic small molecules. Clinical implications may arise when potentially neurotoxic drugs gain enhanced access to the central nervous system under inha-lational anesthetics.