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Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood–Brain Barrier Through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss

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Abstract

The only food and drug administration (FDA)-approved drug currently available for the treatment of acute ischemic stroke is tissue plasminogen activator (tPA), yet the therapeutic benefits of this drug are partially outweighed by the increased risk of hemorrhagic transformation (HT). Analysis of the NIH trial has shown that cigarette smoking protected tPA-treated patients from HT; however, the underlying mechanism is not clear. Nicotinic acetylcholine receptors (nAChR) has shown anti-inflammatory effect and modulation nAChR could be a strategy to reduce ischemia/reperfusion-induced blood–brain barrier (BBB) damage. Since melatonin could regulate the expression of α7nAchR and melatonin’s neuroprotective effect against ischemic injury is mediated via α7nAChR modulation, here, we aim to test the hypothesis that melatonin reduces ischemia and reperfusion (I/R)-induced BBB damage through modulation of α7nACh receptor (α7nAChR). Mice were subjected to 1.5 h ischemia and 24 h reperfusion and at the onset of reperfusion, mice received intraperitoneal administration (i.p.) of either drug or saline. Mice were randomly assigned into five groups: Saline; α7nAChR agonist PNU282987; Melatonin; Melatonin+Methyllycaconitine (MLA, α7nAChR antagonist), and MLA group. BBB permeability was assessed by detecting the extravasation of Evan’s blue and IgG. Our results showed that I/R significantly increased BBB permeability accompanied by occludin degradation, microglia activation, and high mobility group box 1 (HMGB1) release from the neuron. In addition, I/R significantly induced neuronal loss accompanied by the decrease of CREB-regulated transcriptional coactivator 1 (CRTC1) and p-CREB expression. Melatonin treatment significantly inhibited the above changes through modulating α7nAChR. Taken together, these results demonstrate that melatonin provides a protective effect on ischemia/reperfusion-induced BBB damage, at least in part, depending on the modulation of α7nAChR.

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Data Availability

The data are available from the corresponding author upon reasonable request

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81870973, 81671145, 81701316, 81573750, 81473491), Jiangsu Provincial College of Natural Science research project (17KJB180012), by Suzhou Science and Technology for People’s Livelihood (sys2018025). This work was also supported by the Open Project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine) (Grant No WDCM2019007).

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  1. Shuang Chen, Yanyun Sun and Fei Li contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Shuang Chen & Guo-qing Zheng

  2. Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Yanyun Sun, Xinyu Zhang & Xinchun Jin

  3. Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, 442000, China

    Fei Li

  4. Department of Anatomy, Histology and Embrology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China

    Xiaoyan Hu, Xiaoyun Zhao, Yixuan Li, Hui Li & Xinchun Jin

  5. Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100054, China

    Jianliang Zhang

  6. The Central Laboratory, Shenzhen Second People’s Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen University School of Medicine, Shenzhen, 518035, China

    Wenlan Liu

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Contributions

GQZ and XJ are the principal investigators at the two collaborating institutions and are responsible for project design, supervision of technical personnel, interpretation of results, and preparation of manuscript drafts. HL, JZ, and WLL provided advice on experimental design and interpretation and comments on the manuscript. SC,YS, FL, XZHANG, XH, XZHAO, and YL performed experiments, analyzed the data, made the figures, and drafted the manuscript.

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Correspondence to Guo-qing Zheng or Xinchun Jin.

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Chen, S., Sun, Y., Li, F. et al. Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood–Brain Barrier Through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss. Cell Mol Neurobiol 42, 2407–2422 (2022). https://doi.org/10.1007/s10571-021-01122-2

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  • DOI: https://doi.org/10.1007/s10571-021-01122-2

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