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Farrerol Alleviates Cerebral Ischemia–Reperfusion Injury by Promoting Neuronal Survival and Reducing Neuroinflammation

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Abstract

Ischemia–reperfusion (I/R) injury is a key influencing factor in the outcome of stroke. Inflammatory response, oxidative stress, and neuronal apoptosis are among the main factors that affect the progression of I/R injury. Farrerol (FAR) is a natural compound that can effectively inhibit the inflammatory response and oxidative stress. However, the role of FAR in cerebral I/R injury remains unknown. In this study, we found that FAR reduced brain injury and neuronal viability after cerebral I/R injury. Meanwhile, administration of FAR also reduced the inflammatory response of microglia after brain injury. Mechanistically, FAR treatment directly reduced neuronal death after oxygen glucose deprivation/re-oxygenation (OGD/R) through enhancing cAMP-response element binding protein (CREB) activation to increase the expression of downstream neurotrophic factors and anti-apoptotic genes. Moreover, FAR decreased the activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, inhibited microglia activation, and reduced the production of inflammatory cytokines in microglia after OGD/R treatment or LPS stimulation. The compromised inflammatory response by FAR directly promoted the survival of neurons after OGD/R. In conclusion, FAR exerted a protective effect on cerebral I/R injury by directly decreasing neuronal death through upregulating CREB expression and attenuating neuroinflammation. Therefore, FAR could be a potentially effective drug for the treatment of cerebral I/R injury.

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Data Availability

All data generated or analyzed during this study are included in this published article. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

I/R:

Ischemia-reperfusion

FAR:

Farrerol

ROS:

Reactive oxygen species

ERK:

Extracellular signal-regulated kinase

CREB:

CAMP-response element binding protein

MAPK:

Mitogen-activated protein kinase

HR:

Homologous recombination

ECA:

External carotid artery

MCA:

Middle cerebral artery

rCBF:

Regional cerebral blood flow

tMCAO:

Transient middle cerebral artery occlusion

mNSS:

Modified Neurological Severity Scores

OGD/R:

Oxygen glucose deprivation/re-oxygenation

BSA:

Bovine serum albumin

qRT-PCR:

Quantitative real-time PCR

LDH:

Lactate dehydrogenase

LPS:

Lipopolysaccharide

PFA:

Paraformaldehyde

RT:

Room temperature

PBS:

Phosphate-buffered solution

PI:

Propidium iodide

TTC:

2,3,5-Triphenyltetrazolium chloride

DAPI:

Dye 4′,6-diamidino-2-phenylindole

MFI:

Mean fluorescence intensity

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Funding

This work was supported by Science and Technology Support Plan for Youth Innovation of Colleges and Universities of Shandong Province of China (Grant number 2022KJ146, Yu Cui) and Natural Science Foundation of Shandong Province (Grant number ZR202102190696, Rui Xu). Rui Xu also received research support from the Project of Bei**g DNVA Foundation.

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  1. Rui Zhao and **n Zhou contributed equally to this work.

Authors and Affiliations

  1. Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Jiangsu Road 16, Qingdao, 266000, Shandong, China

    Rui Zhao, Zhiyuan Zhao, Wenhao Liu, Zhaolong Zhang, Changxin Wang, Tianli Li & Rui Xu

  2. Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Ningxia Road 308, Qingdao, 266071, Shandong, China

    **n Zhou, Mengfei Lv, Qi Wan & Yu Cui

  3. Qingdao Medical College, Qingdao University, Qingdao, 266071, China

    Rui Zhao, **n Zhou, Zhiyuan Zhao, Wenhao Liu, Mengfei Lv, Changxin Wang, Tianli Li, Zixiong Yang, Rui Xu & Yu Cui

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Contributions

All authors contributed to the study. R. Zhao and X. Zhou designed the research and wrote the first draft of the manuscript. Z. Zhao and W. Liu prepared the material. R. Zhao, M. Lv, Z. Zhang, and C. Wang performed the experiments. X. Zhou, T. Li, Z. Yang, and Q. Wan collected and analyzed the data. R. Xu and Y. Cui conceptualized the research and directed the study. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Rui Xu or Yu Cui.

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All animal experiments were conducted in compliance with National Institutes of Health Guidelines and were approved by the Qingdao University Laboratory Animal Welfare Ethics Committee (July 23, 2021/ No. 20210820C572720220520068).

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Zhao, R., Zhou, X., Zhao, Z. et al. Farrerol Alleviates Cerebral Ischemia–Reperfusion Injury by Promoting Neuronal Survival and Reducing Neuroinflammation. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04031-9

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