喹硫平可保护创伤性脑损伤的血脑屏障。
Quetiapine protects the blood-brain barrier in traumatic brain injury.
机构信息
From the Department of Surgery, Scott and White Medical Center and Texas A&M University Health Science Center College of Medicine.
出版信息
J Trauma Acute Care Surg. 2018 Nov;85(5):968-976. doi: 10.1097/TA.0000000000002011.
BACKGROUND
The integrity of the blood-brain barrier (BBB) is paramount in limiting vasogenic edema following traumatic brain injury (TBI). The purpose of this study was to ascertain if quetiapine, an atypical antipsychotic commonly used in trauma/critical care for delirium, protects the BBB and attenuates hyperpermeability in TBI.
METHODS
The effect of quetiapine on hyperpermeability was examined through molecular modeling, cellular models in vitro and small animal models in vivo. Molecular docking was performed with AutoDock Vina to matrix metalloproteinase-9. Rat brain microvascular endothelial cells (BMECs) were pretreated with quetiapine (20 μM; 1 hour) followed by an inflammatory activator (20 μg/mL chitosan; 2 hours) and compared to controls. Immunofluorescence localization for tight junction proteins zonula occludens-1 and adherens junction protein β-catenin was performed. Human BMECs were grown as a monolayer and pretreated with quetiapine (20 μM; 1 hour) followed by chitosan (20 μg/mL; 2 hours), and transendothelial electrical resistance was measured. C57BL/6 mice (n = 5/group) underwent mild to moderate TBI (controlled cortical impactor) or sham craniotomy. The treatment group was given 10 mg/kg quetiapine intravenously 10 minutes after TBI. The difference in fluorescence intensity between intravascular and interstitium (ΔI) represented BBB hyperpermeability. A matrix metalloproteinase-9 activity assay was performed in brain tissue from animals in the experimental groups ex vivo.
RESULTS
In silico studies showed quetiapine thermodynamically favorable binding to MMP-9. Junctional localization of zonula occludens-1 and β-catenin showed retained integrity in quetiapine-treated cells as compared with the chitosan group in rat BMECs. Quetiapine attenuated monolayer permeability compared with chitosan group (p < 0.05) in human BMECs. In the animal studies, there was a significant decrease in BBB hyperpermeability and MMP-9 activity when compared between the TBI and TBI plus quetiapine groups (p < 0.05).
CONCLUSION
Quetiapine treatment may have novel anti-inflammatory properties to provide protection to the BBB by preserving tight junction integrity.
LEVEL OF EVIDENCE
level IV.
背景
血脑屏障（BBB）的完整性对于限制创伤性脑损伤（TBI）后的血管源性水肿至关重要。本研究的目的是确定在创伤/重症监护中用于治疗谵妄的非典型抗精神病药喹硫平是否能保护 BBB 并减轻 TBI 中的通透性增加。
方法
通过分子建模、体外细胞模型和体内小动物模型来研究喹硫平对通透性的影响。用 AutoDock Vina 对基质金属蛋白酶-9 进行分子对接。用 20 μM 的喹硫平（1 小时）预处理大鼠脑微血管内皮细胞（BMEC），然后用 20 μg/mL 的壳聚糖（2 小时）进行炎症激活，并与对照组进行比较。进行紧密连接蛋白闭合蛋白-1 和黏着连接蛋白 β-连环蛋白的免疫荧光定位。将人 BMEC 培养成单层，用 20 μM 的喹硫平（1 小时）预处理，然后用 20 μg/mL 的壳聚糖（2 小时）处理，测量跨内皮电阻。C57BL/6 小鼠（n = 5/组）接受轻度至中度 TBI（皮质撞击器）或假手术。治疗组在 TBI 后 10 分钟静脉注射 10mg/kg 喹硫平。血管内和间质之间荧光强度的差异（ΔI）代表 BBB 通透性增加。在实验组动物的脑组织中进行基质金属蛋白酶-9 活性测定。
结果
计算机模拟研究表明，喹硫平与 MMP-9 具有热力学上有利的结合。与壳聚糖组相比，大鼠 BMEC 中喹硫平处理的细胞中闭合蛋白-1 和 β-连环蛋白的连接定位显示其完整性得到保留。与壳聚糖组相比，喹硫平降低了人 BMEC 的单层通透性（p < 0.05）。在动物研究中，与 TBI 组相比，TBI 加喹硫平组的 BBB 通透性和 MMP-9 活性显著降低（p < 0.05）。
结论
喹硫平治疗可能具有新的抗炎特性，通过维持紧密连接的完整性来保护 BBB。
证据水平
IV 级。
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