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Int. J. Mol. Sci. 2017, 18(1), 50; doi:10.3390/ijms18010050

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

1
Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy
2
Institute of Human Physiology, Medical School, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
3
Department of Neurosurgery, Regina Elena National Cancer Institute, 00144 Rome, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Hari Shanker Sharma and Aruna Sharma
Received: 23 November 2016 / Revised: 18 December 2016 / Accepted: 22 December 2016 / Published: 28 December 2016
(This article belongs to the Special Issue Blood–Brain Barrier in CNS Injury and Repair)
View Full-Text   |   Download PDF [3203 KB, uploaded 28 December 2016]   |  

Abstract

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. View Full-Text
Keywords: bevacizumab; bilirubin; bilirubin-induced neurologic dysfunction; blood–brain barrier; in vivo bioluminescence imaging; hyperbilirubinemia; kernicterus; luciferase; transgenic mice bevacizumab; bilirubin; bilirubin-induced neurologic dysfunction; blood–brain barrier; in vivo bioluminescence imaging; hyperbilirubinemia; kernicterus; luciferase; transgenic mice
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Manni, I.; Di Rocco, G.; Fusco, S.; Leone, L.; Barbati, S.A.; Carapella, C.M.; Grassi, C.; Piaggio, G.; Toietta, G. Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging. Int. J. Mol. Sci. 2017, 18, 50.

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