RT Journal Article
SR Electronic
T1 Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 84
OP 93
DO 10.1124/mol.115.098228
VO 89
IS 1
A1 Andreia Barateiro
A1 Shujuan Chen
A1 Mei-Fei Yueh
A1 Adelaide Fernandes
A1 Helena Sofia Domingues
A1 João Relvas
A1 Olivier Barbier
A1 Nghia Nguyen
A1 Robert H. Tukey
A1 Dora Brites
YR 2016
UL http://molpharm.aspetjournals.org/content/89/1/84.abstract
AB 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.