Effects of C1 Esterase Inhibitor on Lipid Metabolomic Biomarkers in Hypoxic Neonatal Mice

Background/Purpose: Hypoxia-Ischemia (HI) adversely affects blood–brain barrier (BBB) function. In neonatal hypoxic mice, C1 esterase inhibitor (C1-INH) treatment abolished BBB damage and brain oedema, but the underlying mechanism is unknown. We hypothesized that C1-INH affects the metabolism of phospholipids, playing a major role in vascular and BBB stability.

Methods: P7-C57BL6/N mice, exposed to hypoxia (8% FiO₂, 6 hours), were treated with C1-INH (7.5–30 IU/10 mL/kg, i.p.; Berinert, CSL Behring) or NaCl 0.9% (VT). After a 24 hours-regeneration period, samples were collected. Untargeted LC-MS (METAB, FAU Erlangen) was performed to obtain individual biochemical fingerprints of controls and C1-INH-treated mice. Initially, metabolites of EDTA in plasma were analysed; raw data were processed and analysed (PCA, PLS-DA, t-test) prior to metabolite and pathway enrichment analysis was conducted.

Results: A total of 1,791 metabolites, including 487 lipids (43% fatty acyls, 32% glycerophospho-, 10% sterol-, 5% sphingo-, and 4% glycerolipids) were identified. PCA scores plots effectively distinguish hypoxia and C1-INH samples from controls. Comparing hypoxia-exposed VT- and C1-INH-treated mice, 164 differentially expressed metabolites were identified. The top 20 pathways involved the biosynthesis of glycerophospholipids and phosphatidylcholine as well as sphingolipids.

Conclusion: Present data demonstrate that C1-INH affects the metabolism of glycerophospholipids, including BBB-specific proteins in the developing brain. Further studies on CNS tissue are ongoing to specify robust biomarkers and neuroprotective treatment effects.

Publikationsverlauf

Artikel online veröffentlicht:
26. September 2025