Serum 24S-hydroxycholesterol predicts long-term brain structural and functional outcomes after hypoxia-ischemia in neonatal mice

• Published in: Journal of cerebral blood flow and metabolism Vol. 41; no. 2; pp. 312 - 323
• Main Authors: Lu, Fuxin, Fan, Shujuan, Romo, Andrea R, Xu, Duan, Ferriero, Donna M, Jiang, Xiangning
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.02.2021
• Subjects: Original; brain development; Biomarkers; hypoxia-ischemia; neonatal brain injury; cholesterol metabolism
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1177/0271678X20911910

The major pathway of brain cholesterol turnover relies on its hydroxylation into 24S-hydroxycholesterol (24S-HC) using brain-specific cytochrome P450 46A1 (CYP46A1). 24S-HC produced exclusively in the brain normally traverses the blood-brain barrier to enter the circulation to the liver for excretion; therefore, the serum 24S-HC level is an indication of cholesterol metabolism in the brain. We recently reported an upregulation of CYP46A1 following hypoxia-ischemia (HI) in the neonatal mouse brain and a correlation between serum 24S-HC levels and acute brain damage. Here, we performed a longitudinal study to investigate whether the serum 24S-HC concentrations predict long-term brain structural and functional outcomes. In postnatal day 9 mice subjected to HI, the serum 24S-HC levels increased at 6 h and 24 h after HI and correlated with the infarct volumes measured histologically or by T2-weighted MRI. The 24 h levels were associated with white matter volume loss quantified by MBP immunostaining and luxol fast blue staining. The animals with higher serum 24S-HC at 6 h and 24 h corresponded to those with more severe motor and cognitive deficits at 35-40 days after HI. These data suggest that 24S-HC could be a novel and early blood biomarker for severity of neonatal HI brain damage and associated functional impairments.