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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Pregabalin | Research

Pregabalin mitigates microglial activation and neuronal injury by inhibiting HMGB1 signaling pathway in radiation-induced brain injury

Authors: Zhan Zhang, Jingru Jiang, Yong He, Jinhua Cai, Jiatian Xie, Minyi Wu, Mengdan Xing, Zhenzhen Zhang, Haocai Chang, Pei Yu, Siqi Chen, Yuhua Yang, Zhongshan Shi, Qiang Liu, Haohui Sun, Baixuan He, Junbo Zeng, Jialin Huang, Jiongxue Chen, Honghong Li, Yi Li, Wei-Jye Lin, Yamei Tang

Published in: Journal of Neuroinflammation | Issue 1/2022

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Abstract

Background

Radiation-induced brain injury (RIBI) is the most serious complication of radiotherapy in patients with head and neck tumors, which seriously affects the quality of life. Currently, there is no effective treatment for patients with RIBI, and identifying new treatment that targets the pathological mechanisms of RIBI is urgently needed.

Methods

Immunofluorescence staining, western blotting, quantitative real-time polymerase chain reaction (Q-PCR), co-culture of primary neurons and microglia, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, enzyme-linked immunosorbent assay (ELISA), and CRISPR–Cas9-mediated gene editing techniques were employed to investigate the protective effects and underlying mechanisms of pregabalin that ameliorate microglial activation and neuronal injury in the RIBI mouse model.

Results

Our findings showed that pregabalin effectively repressed microglial activation, thereby reducing neuronal damage in the RIBI mouse model. Pregabalin mitigated inflammatory responses by directly inhibiting cytoplasmic translocation of high-mobility group box 1 (HMGB1), a pivotal protein released by irradiated neurons which induced subsequent activation of microglia and inflammatory cytokine expression. Knocking out neuronal HMGB1 or microglial TLR2/TLR4/RAGE by CRISPR/Cas9 technique significantly inhibited radiation-induced NF-κB activation and pro-inflammatory transition of microglia.

Conclusions

Our findings indicate the protective mechanism of pregabalin in mitigating microglial activation and neuronal injury in RIBI. It also provides a therapeutic strategy by targeting HMGB1-TLR2/TLR4/RAGE signaling pathway in the microglia for the treatment of RIBI.
Appendix
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Metadata
Title
Pregabalin mitigates microglial activation and neuronal injury by inhibiting HMGB1 signaling pathway in radiation-induced brain injury
Authors
Zhan Zhang
Jingru Jiang
Yong He
Jinhua Cai
Jiatian Xie
Minyi Wu
Mengdan Xing
Zhenzhen Zhang
Haocai Chang
Pei Yu
Siqi Chen
Yuhua Yang
Zhongshan Shi
Qiang Liu
Haohui Sun
Baixuan He
Junbo Zeng
Jialin Huang
Jiongxue Chen
Honghong Li
Yi Li
Wei-Jye Lin
Yamei Tang
Publication date
01-12-2022
Publisher
BioMed Central
Keyword
Pregabalin
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02596-7

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