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Cross-Talk Between Neurons and Astrocytes in Response to Bilirubin: Early Beneficial Effects

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Abstract

Hyperbilirubinemia remains one of the most frequent clinical diagnoses in the neonatal period. This condition may lead to the deposition of unconjugated bilirubin (UCB) in the central nervous system, causing nerve cell damage by molecular and cellular mechanisms that are still being clarified. To date, all the studies regarding bilirubin-induced neurological dysfunction were performed in monotypic nerve cell cultures. The use of co-cultures, where astrocyte-containing culture inserts are placed on the top of neuron cultures, provides the means to directly evaluate the cross-talk between these two different cell types. Therefore, this study was designed to evaluate whether protective or detrimental effects are produced by astrocytes over UCB-induced neurodegeneration. Our experimental model used an indirect co-culture system where neuron-to-astrocyte signaling was established concomitantly with the 24 h exposure to UCB. In this model astrocytes abrogated the well-known UCB-induced neurotoxic effects by preventing the loss of cell viability, dysfunction and death by apoptosis, as well as the impairment of neuritic outgrowth. To this protection it may have accounted the induced expression of the multidrug resistance-associated protein 1 and the 3.5-fold increase in the values of S100B, when communication between both cells was established independently of UCB presence. In addition, the presence of astrocytes in the neuronal environment preserved the UCB-induced increase in glutamate levels, but raised the basal concentrations of nitric oxide and TNF-α although no UCB effects were noticed. Our data suggest that bidirectional signalling during astrocyte-neuron recognition exerts pro-survival effects, stimulates neuritogenesis and sustains neuronal homeostasis, thus protecting cells from the immediate UCB injury. These findings may help explain why irreversible brain damage usually develops only after the first day of post-natal life.

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Acknowledgments

We thank Prof. Claudio Tiribelli, Centro Studio Fegato, Trieste, Italy, for the gift of Mrp1-A23 antibody. This work was supported by the strategic project PEst-OE/SAU/UI4013/2011 and the PTDC/SAU-NEU/64385/2006 grants from Fundação para a Ciência e a Tecnologia (FCT), Lisbon, Portugal (to D. B.). A.S.F. was recipient of a Postdoctoral fellowship (FCT SFRH/BPD/26381/2006) from FCT. The funding organization had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The authors declare that there are no actual or potential conflicts of interest.

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  1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL/CPM), Faculty of Pharmacy, University of Lisbon, Avenida Professor Gama Pinto, 1649-003, Lisbon, Portugal

    Ana Sofia Falcão, Rui F. M. Silva, Ana Rita Vaz, Sandra Leitão Silva, Adelaide Fernandes & Dora Brites

  2. Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    Ana Sofia Falcão, Rui F. M. Silva, Adelaide Fernandes & Dora Brites

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  1. Ana Sofia Falcão
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Correspondence to Dora Brites.

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Falcão, A.S., Silva, R.F.M., Vaz, A.R. et al. Cross-Talk Between Neurons and Astrocytes in Response to Bilirubin: Early Beneficial Effects. Neurochem Res 38, 644–659 (2013). https://doi.org/10.1007/s11064-012-0963-2

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  • DOI: https://doi.org/10.1007/s11064-012-0963-2

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