Perioperative Dexmedetomidine attenuates brain ischemia reperfusion injury possibly via up-regulation of astrocyte Connexin 43

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Abstract

Background

Astrocyte Connexin 43 (Cx43) is essential for the trophic and protective support of neurons during brain ischemia reperfusion (I/R) injury. It is believed that dexmedetomidine participates in Cx43-mediated effects. However, its mechanisms remained unclear. This study aims to address the relationship and regulation among them.

Methods

Adult male Sprague-Dawley rats were allocated to the 90-min right middle cerebral arterial occlusion with or without dexmedetomidine pretreatment (5 μg/kg). Neurological functions were evaluated and brain lesions, as well as inflammatory factors (IL-1β, IL-6, TNF-α), were assessed. Ischemic penumbral cortex was harvested to determine the expression of astrocyte Cx43. Primary astrocytes were cultured to evaluate the effect of dexmedetomidine on Cx43 after oxygen-glucose deprivation.

Results

Dexmedetomidine pretreatment attenuated neurological injury, brain lesions and expression of inflammatory factors (IL-1β, IL-6, TNF-α) after brain ischemia ( P < 0.05). Astrocyte Cx43 was down-regulated by brain I/R injury, both in vivo and in vitro, which were reversed by dexmedetomidine ( P < 0.05). This effect was mediated by the phosphorylation of Akt and GSK-3β. Further studies with LY294002 (PI3K inhibitor) or SB216763 (GSK-3β inhibitor) confirmed the effect of dexmedetomidine on astrocyte Cx43.

Conclusions

Perioperative dexmedetomidine administration attenuates neurological injury after brain I/R injury, possibly through up-regulation of astrocyte Cx43. Activation of PI3K-Akt-GSK-3β pathway might contribute to this protective effect.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12871-020-01211-7.

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Most cited references 37

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Neurotoxic reactive astrocytes are induced by activated microglia

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A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.

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Astrocyte metabolism and signaling during brain ischemia.

John J Rossi, Lee Brady, Claudia Mohr (2007)

Brain ischemia results from cardiac arrest, stroke or head trauma. These conditions can cause severe brain damage and are a leading cause of death and long-term disability. Neurons are far more susceptible to ischemic damage than neighboring astrocytes, but astrocytes have diverse and important functions in many aspects of ischemic brain damage. Here we review three main roles of astrocytes in ischemic brain damage. First, we consider astrocyte glycogen stores, which can defend the brain against hypoglycemic brain damage but may aggravate brain damage during ischemia due to enhanced lactic acidosis. Second, we review recent breakthroughs in understanding astrocytic mechanisms of transmitter release, particularly for those transmitters with known roles in ischemic brain damage: glutamate, D-serine, ATP and adenosine. Third, we discuss the role of gap-junctionally connected networks of astrocytes in mediating the spread of damaging molecules to healthy 'bystanders' during infarct expansion in stroke.

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Author and article information

Contributors

Wenqi Huang: huangwq@mail.sysu.edu.cn

Zhongxing Wang: wzhxing@mail.sysu.edu.cn

Journal

Journal ID (nlm-ta): BMC Anesthesiol

Journal ID (iso-abbrev): BMC Anesthesiol

Title: BMC Anesthesiology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2253

Publication date (Electronic): 7 December 2020

Publication date PMC-release: 7 December 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 299

Affiliations

[1 ]GRID grid.412615.5, Department of Anesthesiology, , The First Affiliated Hospital, Sun Yat-sen University, ; No. 58 Zhongshan 2nd Road, Guangzhou, 510080 Guangdong People’s Republic of China

[2 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Pharmacology, Zhongshan School of Medicine, , Sun Yat-Sen University, ; No. 74 Zhongshan 2nd Road, Guangzhou, 510080 Guangdong People’s Republic of China

[3 ]GRID grid.27755.32, ISNI 0000 0000 9136 933X, Department of Anesthesiology, , University of Virginia, ; 1 Hospital Drive, PO Box 800710, Charlottesville, Virginia 22908-0710 USA

Article

Publisher ID: 1211

DOI: 10.1186/s12871-020-01211-7

PMC ID: 7722427

PubMed ID: 33287729

SO-VID: 5c88981b-9428-48c7-9893-3dd6bf358469

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 1 July 2020

Date accepted : 25 November 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81601711

Award ID: 81971877

Award Recipient : Zhongxing Wang

Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;

Award ID: 2016A030313255

Award Recipient : Zhongxing Wang

Custom metadata

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: brain ischemia,reperfusion injury,dexmedetomidine,astrocytes,connexin 43

Data availability:

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: brain ischemia, reperfusion injury, dexmedetomidine, astrocytes, connexin 43

Perioperative Dexmedetomidine attenuates brain ischemia reperfusion injury possibly via up-regulation of astrocyte Connexin 43

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Cardiovascular Innovations and Applications

Most cited references 37

Neurotoxic reactive astrocytes are induced by activated microglia

Mechanism of activation of protein kinase B by insulin and IGF-1.

Astrocyte metabolism and signaling during brain ischemia.

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