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Neuroprotective Effect of Fisetin Against the Cerebral Ischemia-Reperfusion Damage via Suppression of Oxidative Stress and Inflammatory Parameters

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Abstract

It is well established that inflammatory reactions and oxidative stress play an imperial role in cerebral ischemia-reperfusion pathogenesis. Fisetin is a flavonoid and has an antioxidant and anti-inflammatory effect on various diseases. In this study, we have been working to examine the neuroprotective effect of fisetin in brain injuries triggered by cerebral ischemic-reperfusion and explore the potential role of nuclear factor kappa B (NF-κB) signaling. In vitro, fisetin was examined against the cell viability, lactate dehydrogenase (LDH) leakage, cytokines, and apoptosis after ischemia/reperfusion (I/R) induced in the cells. In vivo, I/R injury was induced in the brain via transient middle cerebral artery occlusion (2 h) and reperfusion (20 h). The infarction area, brain water content, and neurofunctional parameters were also estimated. Inflammatory cytokines and brain injury markers were scrutinized at the end of the study. Fisetin treatment alleviated cell injury and suppressed the inflammatory cytokines (interleukin-1 (IL-1), tumor necrosis factor- α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), interleukin-16 (IL-6), and prostaglandin E2 (PGE2)) and antioxidant parameters in a dose-dependent manner. Fisetin significantly (P < 0.001) reduced the infarct volume, brain water content. Fisetin significantly (P < 0.001) suppressed the neurological parameters and inflammatory cytokines such as IL-1, TNF-α, iNOS, IL-1β, COX-2, IL-6, PGE2, and oxidative markers in a dose-dependent manner. Fisetin significantly (P < 0.001) reduced the inflammatory mediators including NF-κB and intercellular adhesion molecule 1 (ICAM-1). Further studies also showed that fisetin significantly inhibited the NF-κB activity via inflammatory and antioxidant pathways. In conclusion, by suppressing inflammatory cytokines, fisetin protected the brain tissue against I/R injury, and this effect could be due to reduced NF-κB activity.

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Abbreviations

NF-κB:

nuclear factor kappa B

LDH:

lactate dehydrogenase

I/R:

ischemia/reperfusion

IL-1:

interleukin-1

TNF-α:

tumor necrosis factor-α

Inos:

inducible nitric oxide synthase

IL-1β:

interleukin-1β

COX-2:

cyclooxygenase-2

IL-6:

interleukin-6

PGE2 :

prostaglandin E2

MMPs:

matric metalloproteinases

ASIC:

acid-sensing ion channel

ATP:

adenosine triphosphate

ROS:

reactive oxygen species

TLRs:

toll-like receptors

MAPK:

mitogen-activated protein kinase

AlCl3 :

aluminum chloride

DMEM:

Dulbecco’s modified Eagle’s medium

CO2 :

carbon dioxide

PBS:

phosphate buffer saline

15-HETE:

15-hydroxyeicosatetraenoic acid

TMB:

3,3′,5,5′-tetramethylbenzidine

SD:

Sprague-Dawley

MCAO:

middle cerebral artery

EDTA:

ethylenediaminetetraacetic acid

CAT:

catalase

MDA:

malonaldehyde

GSH:

glutathione

GPx:

glutathione peroxidase

GR:

glutathione reductase

SOD:

superoxide dismutase

K+ :

potassium

Na+ :

sodium

PPAR-γ:

peroxisome proliferator–activated receptor gamma

STAT1:

signal transducer and activator of transcription factors and transcription-1

DNA:

deoxyribonucleic acid

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Acknowledgments

The authors are very thankful to the Xi’an No.1 Hospital for providing the necessary facility.

Data and Materials Availability

All the data are provided on the request to the corresponding author.

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Authors and Affiliations

  1. Department of Neurosurgery, Henan Provincial People’s Hospital, Zhengzhou City, 450003, Henan Province, China

    Peng Zhang

  2. Department of Neurosurgery, Xi’an No.1 Hospital, No.30 South Street Powder Lane, Beilin District, Xi’an, 710002, Shaanxi, China

    Jian Cui

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  1. Peng Zhang
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Contributions

P. Z. performed the experimental study. J. C. designed the experimental study and interpreted the data. Both authors equally contributed to the proofreading.

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Correspondence to Jian Cui.

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Zhang, P., Cui, J. Neuroprotective Effect of Fisetin Against the Cerebral Ischemia-Reperfusion Damage via Suppression of Oxidative Stress and Inflammatory Parameters. Inflammation 44, 1490–1506 (2021). https://doi.org/10.1007/s10753-021-01434-x

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