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Neuroprotection of Resveratrol Against Focal Cerebral Ischemia/Reperfusion Injury in Mice Through a Mechanism Targeting Gut-Brain Axis

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Abstract

Increasing evidences have shown that resveratrol could protect the brain from ischemic injury; the mechanisms underlying its neuroprotective effects are multifactorial and not fully understood. It remains unclear whether resveratrol could exert neuroprotection through modulating gut-brain axis, which plays important roles in stroke pathology. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion for 3 days. Resveratrol, when applied immediately after MCAO onset for 3 days, promoted Th1/Th2 balance towards Th2 polarization and skewed Treg/Th17 balance towards Treg in the small intestinal lamina propria (SI-LP), and decreased small intestinal pro-inflammatory cytokines expression through modulating intestinal flora at 3 days post-ischemia (dpi). Resveratrol attenuated cerebral ischemia-induced increase in the epithelial and vascular permeability of small intestine as evidenced by reduced evans blue extravasasion and decreased protein leakage by feces/plasma albumin ratio at 3 dpi. The blood levels of pro-inflammatory cytokines at 3 dpi were also attenuated by resveratrol due to inhibiting intestinal pro-inflammatory immunity and decreasing epithelial and vascular permeability. Resveratrol robustly protected against post-stroke inflammation-induced blood–brain barrier disruption not only in the cortex but also in the striatum at 3 dpi. Furthermore, resveratrol mediated smaller cerebral infarcts and less neurological deficits via decreasing the levels of pro-inflammatory cytokines in the peri-infarct area at 3 dpi. Our results for the first time demonstrated that resveratrol may inhibit systemic post-stroke inflammation and neuroinflammation via modulating intestinal flora-mediated Th17/Tregs and Th1/Th2 polarity shift in SI-LP, which may be one of the mechanisms underlying the neuroprotective effects of resveratrol.

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Abbreviations

dpi:

Days post-ischemia

BBB:

Blood–brain barrier

Treg:

Regulatory T

γδ T:

Gamma delta T

Th17:

T helper type 17

SI-LP:

Small intestinal lamina propria

IFN-γ:

Interferon-γ

IL-17A:

Interleukin-17A

MCAO:

Middle cerebral artery occlusion

TTC:

2,3,5-Triphenyltetrazolium chloride

LPL:

Lamina propria lymphocytes

VAN:

Vancomycin

AC:

Amoxicillin and clavulanic acid

ZO-1:

Zonula occludens 1

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Author notes

  1. Zhongci Dou and Xiongfei Rong contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she East Road, Zhengzhou, 450000, Henan, China

    Zhongci Dou, Erxian Zhao, Lixia Zhang & Yunqi Lv

  2. Department of Anesthesiology, People’s Hospital of Zhengzhou University and Henan Provincial People’s Hospital, Zhengzhou, Henan, China

    Xiongfei Rong

Authors
  1. Zhongci Dou
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  2. Xiongfei Rong
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  3. Erxian Zhao
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  4. Lixia Zhang
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  5. Yunqi Lv
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Contributions

Experimental design: YQL; stroke model, behavioral test, flow cytometry, TTC staining, western blotting, permeability assay, ELISA: ZGD, XFR, EXZ; RT-qPCR, hematoxylin and eosin staining, gut injury score: LXZ; imaging tools: ZCD; data analysis: XFR; wrote article: ZCD.

Corresponding author

Correspondence to Yunqi Lv.

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The authors declare that they have no conflict of interest.

Ethical Approval

All procedures were performed in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) revised 1996 and approved by the Animal Care and Use Committee of The First Affiliated Hospital of Zhengzhou University.

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Informed consent was obtained from all individual participants included in the study.

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Dou, Z., Rong, X., Zhao, E. et al. Neuroprotection of Resveratrol Against Focal Cerebral Ischemia/Reperfusion Injury in Mice Through a Mechanism Targeting Gut-Brain Axis. Cell Mol Neurobiol 39, 883–898 (2019). https://doi.org/10.1007/s10571-019-00687-3

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  • DOI: https://doi.org/10.1007/s10571-019-00687-3

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