Metab Brain Dis. 2026 Jul 16;41(1):165. doi: 10.1007/s11011-026-01931-8.
ABSTRACT
BACKGROUND: Ischemic stroke (IS) is associated with high mortality and disability rates, and secondary neuroinflammation is a key driver of exacerbated neuronal damage. Xenon (Xe) exhibits neuroprotective effects, yet the specific mechanism by which it regulates microglia remains unclear.
METHODS: Public transcriptome datasets of human stroke cortex (GSE56267) and Xe-treated microglia (GSE273575) were analyzed, and key genes were screened using machine learning. An oxygen-glucose deprivation/reoxygenation (OGD/R) model was established with human microglial cells (HMC3). NREP expression, microglial polarization, and inflammatory responses were assessed via Western blot, flow cytometry, and ELISA. HMC3 cells were co-cultured with human cortical neurons using Transwell inserts, and neuronal damage was evaluated by CCK-8 assay, kit-based detection, and flow cytometry. Finally, a middle cerebral artery occlusion (MCAO) model was established in rats to investigate the potential involvement of NREP in the neuroprotective effects of Xe in vivo.
RESULTS: NREP was identified as a key regulatory gene that was downregulated after stroke and upregulated following Xe treatment. In the OGD/R model, Xe upregulated NREP expression in HMC3 cells, inhibited M1 polarization and proinflammatory cytokine release, and this effect could be partially reversed by NREP silencing. Xe-treated HMC3 cells mitigated apoptosis and oxidative stress in co-cultured neurons, which appeared to be, at least in part, dependent on NREP. In MCAO rats, Xe upregulated NREP in the brain and reduced infarct volume and neuroinflammation. Critically, in vivo knockdown of NREP significantly reversed these neuroprotective and anti-inflammatory effects of Xe.
CONCLUSION: Xe treatment upregulated NREP expression, inhibited M1 polarization of microglia and neuroinflammation, and alleviated cerebral ischemia-reperfusion injury in experimental models. These findings suggest that NREP contributes to xenon-mediated neuroprotection and may serve as a potential therapeutic target, providing preliminary experimental evidence for subsequent translational research of IS.
PMID:42461351 | DOI:10.1007/s11011-026-01931-8