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

J Cereb Blood Flow Metab. 2021 Feb;41(2):312-323. doi: 10.1177/0271678X20911910. Epub 2020 Mar 13.

Abstract

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.

Keywords: Biomarkers; brain development; cholesterol metabolism; hypoxia-ischemia; neonatal brain injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Biomarkers / metabolism*
  • Hydroxycholesterols / metabolism*
  • Hypoxia-Ischemia, Brain / metabolism*
  • Male
  • Mice
  • Treatment Outcome

Substances

  • Biomarkers
  • Hydroxycholesterols
  • 24-hydroxycholesterol