Abstract
Background
Bilirubin is produced by the breakdown of hemoglobin and is normally catabolized and excreted. Neurotoxic accumulation of serum bilirubin often occurs in premature infants. The homozygous Gunn rat lacks uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), the enzyme needed to biotransform bilirubin. This rodent model of hyperbilirubinemia emulates many aspects of bilirubin toxicity observed in the human infant. We demonstrate that choline supplementation in early postnatal development is neuroprotective in the choline-restricted Gunn rat, when hyperbilirubinemia is induced on postnatal day 5.
Methods
We first compared behaviors and cerebellar weight of pups born to dams consuming regular rat chow to those of dams consuming choline-restricted diets. Second, we measured behaviors and cerebellar weights of pups born to choline-restricted dams, reared on a choline-restricted diet, supplemented with or without choline, and treated with or without sulfadimethoxine (SDMX).
Results
A choline-restricted diet did not change the behavioral outcomes, but cerebellar weight was reduced in the choline-restricted group regardless of genotype or SDMX administration. SDMX induced behavioral deficits in jj pups, and choline supplementation improved most behavioral effects and cerebellar weight in SDMX-treated jj rats.
Conclusions
These results suggest that choline may be used as a safe and effective neuroprotective intervention against hyperbilirubinemia in the choline-deficient premature infant.
Impact
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This article investigates the effect of neonatal jaundice/bilirubin neurotoxicity on cerebellar-mediated behaviors.
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This article explores the potential use of choline as an intervention capable of ameliorating the effect of bilirubin on the choline-restricted developing brain.
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This article opens the door for future studies on the action of choline in the presence of hyperbilirubinemia, especially in preterm neonates.
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Acknowledgements
This work was supported by the NIH/NICHD R21HD085061.
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J.W.: substantial contributions to analysis and interpretation of data, drafting and revising article critically for important intellectual content, and final approval of the version to be published; N.C.R.: drafting the article or revising it critically for important intellectual content; M.H.: substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; N.T.: substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; C.F.B.: substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published.
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Waddell, J., Rickman, N.C., He, M. et al. Choline supplementation prevents the effects of bilirubin on cerebellar-mediated behavior in choline-restricted Gunn rat pups. Pediatr Res 89, 1414–1419 (2021). https://doi.org/10.1038/s41390-020-01187-7
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DOI: https://doi.org/10.1038/s41390-020-01187-7
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