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Blocking Sympathetic Nervous System Reverses Partially Stroke-Induced Immunosuppression but does not Aggravate Functional Outcome After Experimental Stroke in Rats

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Abstract

Stoke results in activation of the sympathetic nervous system (SNS), inducing systemic immunosuppression. However, the potential mechanisms underlying stroke-induced immunosuppression remain unclear. Here, we determined the SNS effects on functional outcome and explored the interactions among SNS, β-arrestin2 and nuclear factor-κB (NF-κB) after experimental stroke in rats. In the current study, stroke was induced by a transient middle cerebral artery occlusion (MCAO) in rats, and SNS activity was inhibited by intraperitoneal injection of 6-hydroxydopamine HBr (6-OHDA). 7.0 T Micro-MRI and Longa score were employed to assess the functional outcome after stroke. Flow cytometry and ELISA assay were used to measure the expression of MHC class II, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Western blot was conducted to analyze β-arrestin2 and NF-κB protein expression levels after experimental stroke. We found significantly increased infarct volumes and functional impairment after MCAO at different post-surgery time points, which were not aggravated by 6-OHDA treatment. SNS blockade partially reversed the expression of MHC class II after stroke over time, as well as TNF-α and IFN-γ levels in lipopolysaccharide-stimulated macrophages in vitro. Treatment of MCAO rats with SNS-inhibitor significantly diminished NF-κB activation and enhanced β-arrestin2 expression after stroke. This study suggests that pharmacological SNS inhibition dose not aggravate functional outcome after stroke. Stroke-induced immunosuppression may be involved in the SNS–β-arrestin2–NF-κB pathway.

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Abbreviations

SNS:

Sympathetic nervous system

NF-κB:

Nuclear factor-κB

MCAO:

Middle cerebral artery occlusion

TNF-α:

Tumor necrosis factor-α

IFN-γ:

Interferon-γ

LPS:

Lipopolysaccharide

MRI:

Magnetic resonance imaging

SPF:

Specific pathogen-free

6-OHDA:

6-Hydroxydopamine HBr

EDTA:

Ethylenediaminetetraacetate

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

ELISA:

Enzyme-linked immunosorbent assays

AM:

Alveolar macrophage

β2AR:

β2-Adrenergic receptor

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Acknowledgments

This study was supported by the National Nature Science Foundation of China (No. 81271336).

Authors’ contributions

Q.-W.D. participated in the design of the study and performed the statistical analysis. H.W. carried out animal experiments and cell culture. H.Y., F.-L.X. L.Z. and H.-Q.Z. performed other experiments and prepared figures. F.-L.Y. conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

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  1. Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, 87, Dingjiaqiao Road, Nanjing, 210009, China

    Qi-Wen Deng, Heng Yang, Fu-Ling Yan, Huan Wang, Fang-Lan Xing, Lei Zuo & Han-Qing Zhang

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  1. Qi-Wen Deng
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  2. Heng Yang
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Correspondence to Fu-Ling Yan.

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All experimental procedures were conducted in accordance with the US National Institutes of Health guidelines and were approved by the Southeast University Committee for the Use and Care of Animals.

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Deng, QW., Yang, H., Yan, FL. et al. Blocking Sympathetic Nervous System Reverses Partially Stroke-Induced Immunosuppression but does not Aggravate Functional Outcome After Experimental Stroke in Rats. Neurochem Res 41, 1877–1886 (2016). https://doi.org/10.1007/s11064-016-1899-8

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