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Moderate Ethanol-Preconditioning Offers Ischemic Tolerance Against Focal Cerebral Ischemic/Reperfusion: Role of Large Conductance Calcium-Activated Potassium Channel

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Abstract

The mechanism underlying moderate ethanol (EtOH)-preconditioning (PC) against ischemic brain injury remains unclear. We evaluated the role of large conductance calcium-sensitive potassium (BKCa) channels in EtOH-PC. Almost one hundred and ninety normal adult SD rats (8 to 10 weeks, 320–350 g) were enrolled in this study. Ischemic/reperfusion (I/R) brain injury was induced in rats by middle cerebral artery occlusion for 2 h followed by reperfusion for 24 h. EtOH or the BKCa channel opener, NS11021, was administered 24 h before I/R with or without pre-treatment with the BKCa channel blocker, paxilline. Infarct volumes were measured by tissue staining and imaging, and neurological functions were assessed by a scoring system. The expression of BKCa channel subunit α was detected by Western blotting, and cell apoptosis was assessed using staining. Prior (24 h) administration of ethanol that produced a peak plasma concentration of ~ 45 mg/dl in rats would offer neuroprotection after cerebral I/R. In addition, the expression of BKCa channel α-subunit was significantly increased 24 h after EtOH-PC (n = 10; control: 2.00 ± 0.09, EtOH: 1.00 ± 0.06; P < 0.5). Compared to I/R, EtOH-PC enhanced the expression of BKCa channel α-subunit both in the penumbra (n = 10; 24 h: I/R: 1.25 ± 0.10, EtOH-PC + I/R: 1.99 ± 0.12; P < 0.01; 4 h: I/R: 1.03 ± 0.03, EtOH-PC + I/R: 1.49 ± 0.05; P < 0.001) and infarct core (n = 10; 4 h: I/R: 1.04 ± 0.04, EtOH-PC + I/R: 1.42 ± 0.05; P < 0.001), improved the neurological function (n = 10; I/R: 14.00 (12.75–15.00), EtOH-PC + I/R: 7.00 (4.75–8.25); P < 0.001), attenuated the apoptosis (n = 10; I/R: 26.80 ± 0.69, EtOH-PC + I/R: 8.46 ± 0.31; P < 0.001), and decreased the infarct volume (n = 10; I/R: 244.00 ± 26.24, EtOH-PC + I/R: 70.09 ± 14.69; P < 0.001) after experimental cerebral I/R. These changes were reversed by paxilline administration. The moderate EtOH-PC protects against I/R-induced brain damage dependent on the upregulation BKCa channels.

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The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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Acknowledgements

We thank the Department of Neuropharmacology of Beijing Neurosurgical Institute for technical assistance.

Funding

This study was supported by the National Key R&D Program of China 2017YFC1307500, Beijing-Tianjin-Hebei Cooperative Basic Research Program H2018206435, the National Natural Science Foundation of China (81801280 and 81601126).

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Authors and Affiliations

  1. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Yilong Zhao, Huajun Yang, Wei Shan, Anchen Guo & Qun Wang

  2. China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China

    Yilong Zhao, Huajun Yang, Wei Shan, Anchen Guo & Qun Wang

  3. Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Beijing, 100069, China

    Wei Shan, Anchen Guo & Qun Wang

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Contributions

QW designed the study and revised the manuscript. YZ carried out experiments, collected the data, accomplished statistical analysis and drafted the manuscript. HY and WS contributed reagents/materials analysis tools. AG revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

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Correspondence to Qun Wang.

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The animal study was reviewed and approved by The Ethics Committee of the Beijing Tiantan Hospital of Capital Medical University.

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Zhao, Y., Yang, H., Shan, W. et al. Moderate Ethanol-Preconditioning Offers Ischemic Tolerance Against Focal Cerebral Ischemic/Reperfusion: Role of Large Conductance Calcium-Activated Potassium Channel. Neurochem Res 47, 3647–3658 (2022). https://doi.org/10.1007/s11064-022-03661-6

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