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

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.