Blood glucose and β-hydroxybutyrate predict significant brain injury after hypoxia-ischemia in neonatal mice

Sarah Ann Duck; Michelle Nazareth; Abigail Fassinger; Charles Pinto; Genesis Elmore; Michael Nugent; Mark St Pierre; Susan J Vannucci; Raul Chavez-Valdez

doi:10.1038/s41390-024-03461-4

Blood glucose and β-hydroxybutyrate predict significant brain injury after hypoxia-ischemia in neonatal mice

Pediatr Res. 2024 Aug 24. doi: 10.1038/s41390-024-03461-4. Online ahead of print.

Authors

Sarah Ann Duck¹, Michelle Nazareth², Abigail Fassinger², Charles Pinto³, Genesis Elmore², Michael Nugent¹, Mark St Pierre¹, Susan J Vannucci⁴, Raul Chavez-Valdez⁵

Affiliations

¹ Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Johns Hopkins University - School of Medicine, Baltimore, MD, USA.
² Department of Neuroscience, Johns Hopkins University Krieger School of Arts and Sciences, Baltimore, MD, USA.
³ Department of Human Biology, University of Toronto, Toronto, ON, Canada.
⁴ Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA.
⁵ Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Johns Hopkins University - School of Medicine, Baltimore, MD, USA. rchavez2@jhmi.edu.

PMID: 39181984
DOI: 10.1038/s41390-024-03461-4

Abstract

Background: The Vannucci procedure is widely used to model cerebral hypoxic-ischemic (HI) injury in neonatal rodents. Identifying minimally invasive biomarkers linked to brain injury would improve stratification of pups to experimental treatments. We hypothesized that extreme blood glucose (BG) and β-hydroxybutyrate (bHB) levels immediately after HI will correlate with severity of brain injury in this model.

Methods: C57BL6 mice of both sexes underwent the Vannucci procedure with BG and bHB measured immediately after hypoxia. GFAP and α-fodrin were measured to assess injury severity at 4h, P11, P18 and P40. Open field (OF), Y-maze (YM), and Object-location task (OLT) were tested at P40.

Results: Clinical seizures-like stereotypies during hypoxia were associated with lower post-hypoxia BG in HI-injured mice. Low BG after HI was related to higher GFAP expression, higher α-fodrin breakdown, lower residual regional volume, and worse working memory. BG was superior to bHB in ROC analysis with BG threshold of <111 mg/dL providing 100% specificity with 72% sensitivity for hippocampal HI-injury.

Conclusions: Post-hypoxic BG is a minimally invasive screening tool to identify pups with significant HI brain injury in the Vannucci model modified for mice improving our ability to stratify pups to experimental treatments to assess effectiveness.

Impact: End hypoxic-ischemic blood glucose levels are a reliable and inexpensive biomarker to detect hypoxic-ischemic brain injury in mice. Screening with blood glucose levels post-hypoxia allows appropriate stratification of those mouse pups most likely to be injured to experimental treatments improving validity and translatability of the results. These findings provide biological plausibility to the clinical observation that extreme blood glucose levels relate to worse outcomes after hypoxia-ischemia.