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The Protective Effects of Ramelteon Against Isoflurane-Induced Insults and Inflammatory Response in Brain Microvascular Endothelial Cells

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Abstract

Anesthetic-induced cognitive impairment has been observed clinically. The mechanism underlying anesthetic-induced cognitive impairment is closely associated with neuronal apoptosis and neuroinflammation. Ramelteon is a potent and highly selective melatonin receptor agonist that has been used for the treatment of insomnia and has been reported to have an anti-inflammatory effect. In this study, we aimed to investigate the protective effects of Ramelteon against the cytotoxicity induced by isoflurane in brain microvascular endothelial cells. Our results show that Ramelteon ameliorated oxidative stress by suppressing the generation of mitochondrial reactive oxygen species (ROS) in human brain microvascular endothelial cells (HBMVECs). In addition, Ramelteon displayed a robust anti-inflammatory capacity against isoflurane-induced insults and inflammation by reducing the generation of interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), monocyte chemotactic protein 1 (MCP-1), stromal cell-derived factor-1 (SDF-1), matrix metalloproteinase-2 (MMP-2), and MMP-9. Furthermore, Ramelteon reduced the expression of cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Importantly, Ramelteon downregulated the activation of the p38MAPK/NF-κB signaling pathway, which is the key transcriptional regulator in the inflammation process. Our findings in the present study provide new evidence for the use of Ramelteon in the prevention of isoflurane-induced insults in brain endothelial cells.

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Authors and Affiliations

  1. Department of Anesthesiology, The Second Affiliated Hospital of Hainan Medical University, 368 Yehai Av., Longhua District, Haikou, 570311, Hainan, China

    Tao Wang, Zhixin Xu, Xiaofang Chen & Hu Sun

  2. Department of Anesthesiology, Qinghai Women’s and Children’s Hospital, Xi’ning, China

    Zhen Li

  3. Department of Respiratory Medicine, Pingdu People’s Hospital, Pingdu, China

    Shuyun Xia

Authors
  1. Tao Wang
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  2. Zhen Li
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  3. Shuyun Xia
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  4. Zhixin Xu
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  5. Xiaofang Chen
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  6. Hu Sun
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Correspondence to Tao Wang.

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Experiments were designed in accordance with “the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects.” Experimental procedures were approved by the Institutional Ethics Committee at The Second Affiliated Hospital of Hainan Medical University (HMU-2-20180326).

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Wang, T., Li, Z., Xia, S. et al. The Protective Effects of Ramelteon Against Isoflurane-Induced Insults and Inflammatory Response in Brain Microvascular Endothelial Cells. Neurotox Res 39, 677–686 (2021). https://doi.org/10.1007/s12640-020-00309-7

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  • DOI: https://doi.org/10.1007/s12640-020-00309-7

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