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Cross-Talk Between Neurons and Astrocytes in Response to Bilirubin: Adverse Secondary Impacts

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Abstract

Previous studies using monotypic nerve cell cultures have shown that bilirubin-induced neurological dysfunction (BIND) involves apoptosis and necrosis-like cell death, following neuritic atrophy and astrocyte activation, and that glycoursodeoxycholic acid (GUDCA) has therapeutic efficacy against BIND. Cross-talk between neurons and astrocytes may protect or aggravate neurotoxicity by unconjugated bilirubin (UCB). In a previous work we have shown that bidirectional signaling during astrocyte-neuron recognition attenuates neuronal damage by UCB. Here, we investigated whether the establishment of neuron-astrocyte homeostasis prior to cell exposure to UCB was instead associated with a lower resistance of neurons to UCB toxicity, and if the pro-survival properties of GUDCA were replicated in that experimental model. We have introduced a 24 h adaptation period for neuron-glia communication prior to the 48 h treatment with UCB. In such conditions, UCB induced glial activation, which aggravated neuronal damage, comprising increased apoptosis, cell demise and neuritic atrophy, which were completely prevented in the presence of GUDCA. Neuronal multidrug resistance-associated protein 1 expression and tumor necrosis factor-α secretion, although unchanged by UCB, increased in the presence of astrocytes. The rise in S100B and nitric oxide in the co-cultures medium may have contributed to UCB neurotoxicity. Since the levels of these diffusible molecules did not change by GUDCA we may assume that they are not directly involved in its beneficial effects. Data indicate that astrocytes, in an indirect neuron-astrocyte co-culture model and after homeostatic setting regulation of the system, are critically influencing neurodegeneration by UCB, and support GUDCA for the prevention of BIND.

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Acknowledgments

This work was supported by FEDER (COMPETE Programme) and by National funds (FCT—Fundação para a Ciência e a Tecnologia—Projects PTDC/SAU-NEU/64385/2006 to D. B. and PEst-OE/SAU/UI4013/2011 to iMed.UL). A. S. F. holds a a post doctoral research position (C2007-FFUL/UBMBE/02/2011) granted by 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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Authors and Affiliations

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

    Ana Sofia Falcão, Rui F. M. Silva, Ana Rita Vaz, Cátia Gomes, Adelaide Fernandes, Andreia Barateiro & Dora Brites

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

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

  3. Centro Studi Fegato, AREA Science Park, Department of BBCM, University of Trieste, Bld Q, Basovizza Campus, Trieste, Italy

    Claudio Tiribelli

  4. Clinica Patologie Fegato-Liver Clinic, Ospedale Cattinara, Trieste, Italy

    Claudio Tiribelli

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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: Adverse Secondary Impacts. Neurotox Res 26, 1–15 (2014). https://doi.org/10.1007/s12640-013-9427-y

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