Abstract
Background
Neonates have high levels of cold-shock proteins (CSPs) in the normothermic brain for a limited period following birth. Hypoxic–ischemic (HI) insults in term infants produce neonatal encephalopathy (NE), and it remains unclear whether HI-induced pathology alters baseline CSP expression in the normothermic brain.
Methods
Here we established a version of the Rice–Vannucci model in PND 10 mice that incorporates rigorous temperature control.
Results
Common carotid artery (CCA)-ligation plus 25 min hypoxia (8% O2) in pups with targeted normothermia resulted in classic histopathological changes including increased hippocampal degeneration, astrogliosis, microgliosis, white matter changes, and cell signaling perturbations. Serial assessment of cortical, thalamic, and hippocampal RNA-binding motif 3 (RBM3), cold-inducible RNA binding protein (CIRBP), and reticulon-3 (RTN3) revealed a rapid age-dependent decrease in levels in sham and injured pups. CSPs were minimally affected by HI and the age point of lowest expression (PND 18) coincided with the timing at which heat-generating mechanisms mature in mice.
Conclusions
The findings suggest the need to determine whether optimized therapeutic hypothermia (depth and duration) can prevent the age-related decline in neuroprotective CSPs like RBM3 in the brain, and improve outcomes during critical phases of secondary injury and recovery after NE.
Impact
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The rapid decrease in endogenous neuroprotective cold-shock proteins (CSPs) in the normothermic cortex, thalamus, and hippocampus from postnatal day (PND) 11–18, coincides with the timing of thermogenesis maturation in neonatal mice.
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Hypoxia–ischemia (HI) has a minor impact on the normal age-dependent decline in brain CSP levels in neonates maintained normothermic post-injury.
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HI robustly disrupts the expected correlation in RNA-binding motif 3 (RBM3) and reticulon-3 (RTN3).
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The potent neuroprotectant RBM3 is not increased 1–4 days after HI in a mouse model of neonatal encephalopathy (NE) in the term newborn and in which rigorous temperature control prevents the manifestation of endogenous post-insult hypothermia.
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Funding
This work was supported by NIH/NINDS grants R01NS105721 to T.C.J., by the University of South Florida Morsani College of Medicine start-up funds to T.C.J., by a Lloyd Reback Family Gift and T32 (2T32HD040686) to J.R.H., and by the Ake N. Grenvik Chair in Critical Care Medicine to P.M.K.
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T.C.J. conceived the study. T.C.J. and P.M.K. contributed to the study design. T.C.J. and J.R.H. drafted the manuscript. R.H.G., R.D.K., V.A.V., K.G., K.J.-F., and J.S. contributed to experiments and data acquisition. T.C.J., P.M.K., R.H.G., and J.R.H. contributed to data analysis. R.H.G., R.D.K., V.A.V., K.G., K.J.-F., and J.S. edited the draft and contributed to the final submitted version.
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T.C.J. and P.M.K. are co-inventors on a USPTO Application (No. 15/573,006) titled: “Method to Improve Neurologic Outcomes in Temperature Managed Patients.”
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Jackson, T.C., Herrmann, J.R., Garman, R.H. et al. Hypoxia–ischemia-mediated effects on neurodevelopmentally regulated cold-shock proteins in neonatal mice under strict temperature control. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-01990-4
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DOI: https://doi.org/10.1038/s41390-022-01990-4
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