Influx of Metabolites into Cerebrospinal Fluid in Intracerebral Hemorrhage is Associated with Increased Central Inflammation: a Retrospective Observational Study.

Abstract

Intracerebral hemorrhage (ICH) is characterized by the rupture of blood vessels, allowing components from peripheral circulation to infiltrate the brain and impair central immune functions. This study employs non-targeted metabolomics to compare cerebrospinal fluid (CSF) metabolites between acute-phase and recovery-phase of ICH, aiming to identify metabolites associated with ICH central inflammation. CSF and plasma samples were collected from a retrospective observational cohort of participants with ICH (n = 38). Additionally, we obtained CSF samples from patients who underwent lower limb surgery due to accidental injuries, serving as healthy controls (n = 12). Non-targeted metabolomics analysis was performed, and inflammatory factors in the CSF were measured. The association between these metabolites and inflammation in the CSF was validated using a collagenase-induced ICH mouse model and microglial cultures in vitro. Our results demonstrate that the levels of certain metabolites in the cerebrospinal fluid of ICH patients changed significantly from the acute phase to the recovery phase (P < 0.05, VIP > 1). Furthermore, the concentration of inflammatory factors in the acute-phase CSF was significantly higher compared to both the recovery phase of ICH and healthy control levels. Correlation analyses of inflammatory factors and the patients' CSF metabolites revealed several metabolites associated with central inflammation. Notably, kynurenic acid (Kyna) exhibited a positive correlation with central inflammation and a negative correlation with the Glasgow Coma Scale (GCS). In the collagenase-induced ICH mouse model, elevated levels of Kyna were also associated with increased inflammation in the CSF. Additionally, in vitro studies demonstrated that Kyna regulates inflammatory cytokines by activating microglia. Our study highlights a significant relationship between metabolites in the CSF of ICH patients and central inflammation. Specifically, Kyna promotes inflammation by activating microglia, suggesting its potential as a promising target for therapeutic intervention in ICH central inflammation. Registration: 2023-KY-155-02.