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Topiramate Reverses Physiological and Behavioral Alterations by Postoperative Cognitive Dysfunction in Rat Model Through Inhibiting TNF Signaling Pathway

  • Wenjie Su
  • Min Xie
  • Yao Li
  • Xinran Gong
  • Jiacen LiEmail author
Original Paper

Abstract

This study aimed to investigate the effects of topiramate (TPM) on rats with postoperative cognitive dysfunction (POCD) and elucidate the underlying mechanism. Differentially expressed genes in propofol-treated group and vehicle control group were filtered out and visualized in heatmap based on R program. POCD rat models were established for validation of TPM’s anti-inflammatory action and Morris water maze (MWM) test was employed for assessment of spatial learning and memory ability of rats. Hematoxylin and eosin (HE) staining was applied to detect the neurodegeneration, and the apoptosis status was detected using TUNEL assay. In vitro, hippocampal microglia was treated with lipopolysaccharide or TPM to validate the TPM’s anti-inflammatory action. Cell apoptosis was detected with flow cytometry. Inflammatory factors were detected by enzyme-linked immunosorbent assay, and factor-associated suicide (Fas), Fas-associated protein with death domain (FADD) expression were detected by western blot. As results, TPM administration improved the spatial learning and memory ability in POCD rat by decreasing the expression levels of Fas, FADD, and inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-1β, IL-1β; interleukin-6, IL-6) in POCD rats. In addition, TPM down-regulated cell apoptotic rate to suppress POCD by decreasing the expression of Caspase8, Bcl2-associated X (Bax), and poly ADP-ribose polymerase-1 (PARP1) yet enhancing B-cell lymphoma-2 (Bcl-2) expression. Besides, inhibition of Fas enhanced TPM-induced down-regulation of apoptosis of neuronal cell in hippocampus tissues of POCD rats. Our results revealed that treatment of POCD rats with TPM could suppress neuronal apoptosis in the hippocampus tissues, and the neuroprotective effects of TPM may relate with the regulation of tumor necrosis factor (TNF) signaling pathway.

Keywords

Topiramate Postoperative cognitive dysfunction Propofol TNF signaling pathway Neuroinflammation Apoptosis Fas/Fas-L 

Abbreviations

ANOVA

Analysis of variance

APC

Allophycocyanin

BBB

Blood–brain barrier

Bax

Bcl2-associated X

Bcl-2

B-cell lymphoma-2

DAB

Diaminobenzidine

ELISA

Enzyme-linked immunosorbent assay

FADD

Fas-associated protein with death domain

GABA

Gamma-aminobutyric acid

GEO

Gene expression omnibus

GSEA

Gene set enrichment analysis

HRP

Horseradish peroxidase

HE

Hematoxylin and eosin

IgG

Immunoglobulin G

LPS

Lipopolysaccharide

LL

Lower left

LR

Lower right

MAPK

Mitogen-activated protein kinase

MWM

Morris water maze

PARP1

Poly ADP-ribose polymerase-1

PI

Propidium iodide

POCD

Postoperative cognitive dysfunction

SD

Standard deviation

TNF

Tumor necrosis factor

TPM

Topiramate

TUNEL

TdT-mediated dUTP Nick-End labeling

UL

Upper left

UR

Upper right

Notes

Authors Contributions

Contributing to the conception and design: WS, JL, and MX; Analyzing and interpreting the data: YL, MX, and XG; drafting the article: WS, YL, and JL; revising it critically for important intellectual content: JL, XG, and WS; and approving the final version to be published: All authors.

Funding

None.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors. All procedures performed in studies involving animals were in accordance with the ethical standards of Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital.

Informed Consent

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

Supplementary material

12017_2019_8578_MOESM1_ESM.docx (22 kb)
Supplementary material 1 (DOCX 21 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologySichuan Academy of Medical Sciences & Sichuan Provincial People’s HospitalChengduChina

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