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Midazolam Ameliorates Impairment of the Blood–Brain Barrier (BBB) Against LPS

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Abstract

Central nervous system (CNS) dysfunction induced by sepsis and pathogenic microbial infections is reported to be closely associated with increased permeability of the blood–brain barrier (BBB), which is mainly mediated by the stimulation of lipopolysaccharide (LPS) on inflammatory signaling. Midazolam is a novel sedative acting on the benzodiazepine receptor, which is recently reported to exert a neuroprotective effect by inhibiting inflammation. The present study will explore the potential repair capacity of Midazolam on LPS-induced damage to the BBB. The in vivo mice model was established by intraperitoneal injection of LPS, while the in vitro model was constructed by stimulating endothelial cells utilizing LPS. We found that the increased malondialdehyde (MDA) level and reduced superoxide dismutase (SOD) activity in the brain cortices, promoted serum concentration of inflammatory factors, and elevated BBB permeability were found in the LPS group, all of which were dramatically reversed by 1 mg/kg and 2 mg/kg Midazolam. Interestingly, Midazolam increased the expression of the tight junction protein zonula occludens-1 (ZO-1). In LPS-challenged in vitro human brain microvascular endothelial cells (HBMECs), the increased concentration of inflammatory factors, reduced trans-endothelial electrical resistance (TEER) level, elevated relative value of trans-endothelial permeability, and downregulated ZO-1 were observed, all of which were pronouncedly alleviated by Midazolam, accompanied by the inhibition on the Ras homolog family member A/ Rho-kinase 2 (RhoA/ROCK-2) pathway. Furthermore, the regulatory effects of Midazolam on ZO-1 expression and the endothelial monolayer permeability in LPS-challenged HBMECs were abolished by the overexpression of RhoA. Collectively, our data imply that Midazolam ameliorated the impairment of the BBB against LPS by regulating the RhoA/ROCK2 pathway.

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Data Availability Statement/Availability of Data Materials

Data of this study are available upon reasonable request to the corresponding authors.

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Funding

This study was supported by the “Peking Union Medical College, Chinese Academy of Medical Sciences” and "Nantong Municipal Health Committee (MB2020024)".

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Authors and Affiliations

  1. Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China

    Juyan Zheng, Kai He & Xuerong Yu

  2. Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Bejing, 100730, China

    Wei Zhang

  3. Department of Anesthesiology, Affiliated Tumor Hospital of Nantong University, Nantong, 226006, China

    PeiPei Kang

  4. Department of Blood Transfusion, The First Affiliated Hospital of Baotou Medical College, Baotou, 014017, China

    Xiaojiao Zheng

  5. Department of Anesthesiology, Wuhai People’s Hospital, Wuhai, 016099, China

    Hong Bai

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  1. Juyan Zheng
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  2. Wei Zhang
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  3. PeiPei Kang
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  4. Xiaojiao Zheng
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  5. Kai He
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  7. Xuerong Yu
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Contributions

Juyan Zheng and Xuerong Yu contributed to experimental design and data analysis; Juyan Zheng, Wei Zhang, PeiPei Kang, Xiaojiao Zheng, Kai He, and Hong Bai contributed to investigation; Xuerong Yu prepared the manuscript. All authors have read and approved the manuscript.

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Correspondence to Xuerong Yu.

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Zheng, J., Zhang, W., Kang, P. et al. Midazolam Ameliorates Impairment of the Blood–Brain Barrier (BBB) Against LPS. Neurotox Res 40, 751–762 (2022). https://doi.org/10.1007/s12640-022-00508-4

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  • DOI: https://doi.org/10.1007/s12640-022-00508-4

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