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. 2025 Sep;62(9):11382-11402.
doi: 10.1007/s12035-025-04950-1. Epub 2025 Apr 25.

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

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

Yongkang Fang et al. Mol Neurobiol. 2025 Sep.

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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Conflict of interest statement

Declarations. Ethics Approval: All animal experimental protocols were authorized by the Institutional Animal Care and Use Committee of Tongji Medical College, Huazhong University of Science and Technology (Ethics approval number: TJH- 202001002). Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing interests: The authors declare no competing interests.

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