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Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging

Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we no...

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Autores principales: Manni, Isabella, Di Rocco, Giuliana, Fusco, Salvatore, Leone, Lucia, Barbati, Saviana Antonella, Carapella, Carmine Maria, Grassi, Claudio, Piaggio, Giulia, Toietta, Gabriele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297685/
https://www.ncbi.nlm.nih.gov/pubmed/28036021
http://dx.doi.org/10.3390/ijms18010050
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author Manni, Isabella
Di Rocco, Giuliana
Fusco, Salvatore
Leone, Lucia
Barbati, Saviana Antonella
Carapella, Carmine Maria
Grassi, Claudio
Piaggio, Giulia
Toietta, Gabriele
author_facet Manni, Isabella
Di Rocco, Giuliana
Fusco, Salvatore
Leone, Lucia
Barbati, Saviana Antonella
Carapella, Carmine Maria
Grassi, Claudio
Piaggio, Giulia
Toietta, Gabriele
author_sort Manni, Isabella
collection PubMed
description Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood–brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction.
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spelling pubmed-52976852017-02-10 Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging Manni, Isabella Di Rocco, Giuliana Fusco, Salvatore Leone, Lucia Barbati, Saviana Antonella Carapella, Carmine Maria Grassi, Claudio Piaggio, Giulia Toietta, Gabriele Int J Mol Sci Article Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood–brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction. MDPI 2016-12-28 /pmc/articles/PMC5297685/ /pubmed/28036021 http://dx.doi.org/10.3390/ijms18010050 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Manni, Isabella
Di Rocco, Giuliana
Fusco, Salvatore
Leone, Lucia
Barbati, Saviana Antonella
Carapella, Carmine Maria
Grassi, Claudio
Piaggio, Giulia
Toietta, Gabriele
Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging
title Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging
title_full Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging
title_fullStr Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging
title_full_unstemmed Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging
title_short Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging
title_sort monitoring the response of hyperbilirubinemia in the mouse brain by in vivo bioluminescence imaging
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297685/
https://www.ncbi.nlm.nih.gov/pubmed/28036021
http://dx.doi.org/10.3390/ijms18010050
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