TY - JOUR T1 - Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.098228 SP - mol.115.098228 AU - Andreia Barateiro AU - Shu-Juan Chen AU - Mei-Fei Yueh AU - Adelaide Fernandes AU - Helena Sofia Domingues AU - Joao Relvas AU - Olivier Barbier AU - Nghia Nguyen AU - Robert H Tukey AU - Dora Brites Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/10/19/mol.115.098228.abstract N2 - Bilirubin-induced neurologic dysfunction (BIND) and kernicterus has been used to describe moderate to severe neurological dysfunction observed in children exposed to excessive levels of total serum bilirubin (TCB) 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 CNS toxicity. The accumulation of TCB in these mice leads to diffuse yellow coloration of brain tissue and a marked cerebellar hypoplasia that we characterize as kernicterus. Histological 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 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 most affected area with greater myelination impairment and glia burden, showing a marked loss of Purkinje cells and a 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 neurological sequelae observed after severe hyperbilirubinemia. ER -