TREK- 1 Ameliorates Secondary Brain Injury by Regulating Inflammatory Microenvironment via CX3 CL1-CX3 CR1 Pathway After Intracerebral Hemorrhage

  • Mol Neurobiol. 2025 Apr 25. doi: 10.1007/s12035-025-04950-1.
Yongkang Fang  1  2 ,  Dilinuer Sadike  1  3 ,  Na Jiang  1  2 ,  Yuan Xu  1  2 ,  Yao Wang  1  2 ,  Yang Liu  1  2 ,  Xiaolong Zheng  1  2 ,  Zhou Zhu  1  2 ,  Suiqiang Zhu  1  2 ,  Wei Wang  1  2 ,  Feng Xu  4  5 ,  Minjie Xie  6  7
Affiliations
  • 1. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, Hubei, China.
  • 2. Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, 430030, Wuhan, China.
  • 3. Hami Central Hospital, 11 Square North Road, 835000, Hami, Xinjiang, China.
  • 4. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, Hubei, China. [email protected].
  • 5. Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, 430030, Wuhan, China. [email protected].
  • 6. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, Hubei, China. [email protected].
  • 7. Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, 430030, Wuhan, China. [email protected].
PMID: 40279035 DOI: 10.1007/s12035-025-04950-1
Abstract

Neuroinflammation plays a pivotal role in the pathogenesis of secondary brain injury (SBI) after intracerebral hemorrhage (ICH). TREK-1 is a background Potassium Channel, and its role in regulating neuroinflammation after ICH remains unclear. In this study, ICH models were induced in wide-type (WT) and TREK knockout mice via intra-striatal administration of collagenase. Additionally, WT ICH mice were treated with the TREK-1 agonist ML67-33. Immunofluorescence, western blot, quantitative Real-Time PCR, enzyme-linked immunosorbent assay, and RNA-sequencing were performed to determine the role and the mechanism of TREK-1 in regulating neuroinflammation after ICH. The results indicate that TREK-1 deficiency exacerbated microglia/macrophages activation and pro-inflammatory polarization, as well as the influx of inflammatory cytokines and peripheral inflammatory cells compared to WT ICH mice. Conversely, activation of TREK-1 attenuated the inflammatory response and SBI post-ICH. These effects may be mediated through the CX3CL1-CX3CR1 pathway, as validated by specific inhibitors AZD8797. This study identified TREK-1 as a crucial modulator in alleviating SBI by regulating the inflammatory microenvironment via the CX3CL1-CX3CR1 pathway.

Keywords
CX3 CL1-CX3 CR1; Inflammatory microenvironment; Intracerebral hemorrhage; Secondary brain injury; TREK- 1.
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