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Rat Cerebellar Slice Cultures Exposed to Bilirubin Evidence Reactive Gliosis, Excitotoxicity and Impaired Myelinogenesis that Is Prevented by AMPA and TNF-α Inhibitors

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Abstract

The cerebellum is one of the most affected brain regions in the course of bilirubin-induced neurological dysfunction. We recently demonstrated that unconjugated bilirubin (UCB) reduces oligodendrocyte progenitor cell (OPC) survival and impairs oligodendrocyte (OL) differentiation and myelination in co-cultures of dorsal root ganglia neurons and OL. Here, we used organotypic cerebellar slice cultures, which replicate many aspects of the in vivo system, to dissect myelination defects by UCB in the presence of neuroimmune-related glial cells. Our results demonstrate that treatment of cerebellar slices with UCB reduces the number of myelinated fibres and myelin basic protein mRNA expression. Interestingly, UCB addition to slices increased the percentage of OPC and decreased mature OL content, whereas it decreased Olig1 and increased Olig2 mRNA expression. These UCB effects were associated with enhanced gliosis, revealed by an increased burden of both microglia and astrocytes. Additionally, UCB treatment led to a marked increase of tumor necrosis factor (TNF)-α and glutamate release, in parallel with a decrease of interleukin (IL)-6. No changes were observed relatively to IL-1β and S100B secretion. Curiously, both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist and TNF-α antibody partially prevented the myelination defects that followed UCB exposure. These data point to a detrimental role of UCB in OL maturation and myelination together with astrocytosis, microgliosis, and both inflammatory and excitotoxic responses, which collectively may account for myelin deficits following moderate to severe neonatal jaundice.

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Acknowledgements

This work was supported by FEDER (COMPETE Programme) and by National funds (Fundação para a Ciência e a Tecnologia (FCT) project PTDC/SAU-NEU/64385/2006 to D.B. and project PEst-OE/SAU/UI4013/2011 and 2012). A. B. was recipient of a Ph.D. fellowship (SFRH/BD/43885/2008) from FCT. H.S.D. is supported by a Marie Curie Intra European Fellowship within the 7th European Community Framework Programme. Work in the lab of J.B.R. was supported by a PTDC/BIA-BCM/112730/2009 from FCT. The funding organisation had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal

    Andreia Barateiro, Adelaide Fernandes & Dora Brites

  2. Instituto de Biologia Molecular e Celular, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal

    Helena Sofia Domingues & João Bettencourt Relvas

  3. Department of Biochemistry and Human Biology, Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal

    Adelaide Fernandes & Dora Brites

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  1. Andreia Barateiro
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  2. Helena Sofia Domingues
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  3. Adelaide Fernandes
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  4. João Bettencourt Relvas
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  5. Dora Brites
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Correspondence to Adelaide Fernandes.

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Barateiro, A., Domingues, H.S., Fernandes, A. et al. Rat Cerebellar Slice Cultures Exposed to Bilirubin Evidence Reactive Gliosis, Excitotoxicity and Impaired Myelinogenesis that Is Prevented by AMPA and TNF-α Inhibitors. Mol Neurobiol 49, 424–439 (2014). https://doi.org/10.1007/s12035-013-8530-7

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