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Rectal temperature after hypoxia-ischemia predicts white matter and cortical pathology in the near-term ferret

Pediatric Research volume 95, pages 84–92 (2024)Cite this article

Abstract

Background

Neonatal encephalopathy (NE) remains a common cause of infant morbidity and mortality. Neuropathological corollaries of NE associated with acute hypoxia-ischemia include a central injury pattern involving the basal ganglia and thalamus, which may interfere with thermoregulatory circuits. Spontaneous hypothermia (SH) occurs in both preclinical models and clinical hypoxic-ischemic NE and may provide an early biomarker of injury severity. To determine whether SH predicts the degree of injury in a ferret model of hypoxic-ischemic NE, we investigated whether rectal temperature (RT) 1 h after insult correlated with long-term outcomes.

Methods

Postnatal day (P)17 ferrets were presensitized with Escherichia coli lipopolysaccharide before undergoing hypoxia-ischemia/hyperoxia (HIH): bilateral carotid artery ligation, hypoxia-hyperoxia-hypoxia, and right ligation reversal. One hour later, nesting RTs were measured.

Results

Animals exposed to HIH were separated into normothermic (NT; ≥34.4 °C) or spontaneously hypothermic (SH; <34.4 °C) groups. At P42, cortical development, ex vivo MRI, and neuropathology were quantitated. Whole-brain volume and fractional anisotropy in SH brains were significantly decreased compared to control and NT animals. SH brains also had significantly altered gyrification, greater cortical pathology, and increased corpus callosum GFAP staining relative to NT and control brains.

Conclusion

In near-term-equivalent ferrets, nesting RT 1 h after HIH may predict long-term neuropathological outcomes.

Impact

  • High-throughput methods to determine injury severity prior to treatment in animal studies of neonatal brain injury are lacking.

  • In a gyrified animal model of neonatal inflammation-sensitized hypoxic-ischemic brain injury in the ferret, rectal temperature 1 h after hypoxia predicts animals who will have increased cortical pathology and white matter changes on MRI.

  • These changes parallel similar responses in rodents and humans but have not previously been correlated with long-term neuropathological outcomes in gyrified animal models.

  • Endogenous thermoregulatory responses to injury may provide a translational marker of injury severity to help stratify animals to treatment groups or predict outcome in preclinical studies.

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Fig. 1: P17 hypoxic-ischemia timeline.
Fig. 2: Post-insult nesting temperatures.
Fig. 3: Post-HIE body weights.
Fig. 4: Magnetic resonance imaging and diffusion tensor imaging.
Fig. 5: Brain gyrification and cortical pathology.
Fig. 6: Quantitative immunohistochemistry.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank Simar Virk and Annamarie Shearlock for assisting in brain measurements and preparing brains for MRI.

Funding

This work was funded by the Bill and Melinda Gates Foundation.

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Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA, USA

    Olivia R. White, Kylie A. Corry, Daniel H. Moralejo, Janessa B. Law, Ulrike Mietzsch, Sandra E. Juul & Thomas R. Wood

  2. Department of Comparative Medicine, University of Washington, Seattle, WA, USA

    Jessica M. Snyder

  3. Center on Human Development and Disability, University of Washington, Seattle, WA, USA

    Sandra E. Juul & Thomas R. Wood

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Contributions

Data acquisition: O.R.W., K.A.C., D.H.M., J.B.L., J.M.S., T.R.W. Data analysis: O.R.W., T.R.W. Interpretation: O.R.W., U.M., S.E.J., T.R.W. Manuscript drafting: O.R.W., T.R.W. Manuscript editing and revision: O.R.W., K.A.C., D.H.M., J.B.L., J.M.S., U.M., S.E.J.,T.R.W. Approval of final manuscript: O.R.W., K.A.C., D.H.M., J.B.L., J.M.S., U.M., S.E.J., T.R.W.

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Correspondence to Thomas R. Wood.

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White, O.R., Corry, K.A., Moralejo, D.H. et al. Rectal temperature after hypoxia-ischemia predicts white matter and cortical pathology in the near-term ferret. Pediatr Res 95, 84–92 (2024). https://doi.org/10.1038/s41390-023-02793-x

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