Format

Send to

Choose Destination
Mol Pharmacol. 2016 Jan;89(1):84-93. doi: 10.1124/mol.115.098228. Epub 2015 Oct 19.

Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia.

Author information

1
Research Institute for Medicines (iMed.UL) (A.B., A.F., D.B.) and Department of Biochemistry and Human Biology (A.F., D.B.), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal; Laboratory of Environmental Toxicology, Department of Pharmacology, and Chemistry and Biochemistry, University of California San Diego, La Jolla, California (S.C., M-F.Y., N.N., R.H.T.); Departamento de Biologia Experimental, Faculty of Medicine (H.S.D., J.R.) and Instituto de Biologia Molecular e Celular (J.R.), University of Porto, Porto, Portugal; Laboratory of Molecular Pharmacology, CHU de Québec Research Centre and Faculty of Pharmacy, Laval University, Québec, QC, Canada (O.B.).
2
Research Institute for Medicines (iMed.UL) (A.B., A.F., D.B.) and Department of Biochemistry and Human Biology (A.F., D.B.), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal; Laboratory of Environmental Toxicology, Department of Pharmacology, and Chemistry and Biochemistry, University of California San Diego, La Jolla, California (S.C., M-F.Y., N.N., R.H.T.); Departamento de Biologia Experimental, Faculty of Medicine (H.S.D., J.R.) and Instituto de Biologia Molecular e Celular (J.R.), University of Porto, Porto, Portugal; Laboratory of Molecular Pharmacology, CHU de Québec Research Centre and Faculty of Pharmacy, Laval University, Québec, QC, Canada (O.B.) s18chen@ucsd.edu dbrites@ff.ulisboa.pt.

Abstract

Bilirubin-induced neurologic dysfunction (BIND) and kernicterus has been used to describe moderate to severe neurologic dysfunction observed in children exposed to excessive levels of total serum bilirubin (TSB) during the neonatal period. Here we use a new mouse model that targets deletion of the Ugt1 locus and the Ugt1a1 gene in liver to promote hyperbilirubinemia-induced seizures and central nervous system toxicity. The accumulation of TSB in these mice leads to diffuse yellow coloration of brain tissue and a marked cerebellar hypoplasia that we characterize as kernicterus. Histologic studies of brain tissue demonstrate that the onset of severe neonatal hyperbilirubinemia, characterized by seizures, leads to alterations in myelination and glia reactivity. Kernicterus presents as axonopathy with myelination deficits at different brain regions, including pons, medulla oblongata, and cerebellum. The excessive accumulation of TSB in the early neonatal period (5 days after birth) promotes activation of the myelin basic protein (Mbp) gene with an accelerated loss of MBP that correlates with a lack of myelin sheath formation. These changes were accompanied by increased astroglial and microglial reactivity, possibly as a response to myelination injury. Interestingly, cerebellum was the area most affected, with greater myelination impairment and glia burden, and showing a marked loss of Purkinje cells and reduced arborization of the remaining ones. Thus, kernicterus in this model displays not only axonal damage but also myelination deficits and glial activation in different brain regions that are usually related to the neurologic sequelae observed after severe hyperbilirubinemia.

PMID:
26480925
PMCID:
PMC4702100
DOI:
10.1124/mol.115.098228
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center