title: Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging.
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.
authors.affiliation: Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy. isabella.manni@ifo.gov.it.
authors.forename: Isabella
authors.initials: I
authors.lastname: Manni
authors.affiliation: Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy. giuliana.dirocco@ifo.gov.it.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Di Rocco
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica del Sacro Cuore, 00168 Rome, Italy. salvatore.fusco@unicatt.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fusco
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica del Sacro Cuore, 00168 Rome, Italy. lucia.leone@unicatt.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Leone
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica del Sacro Cuore, 00168 Rome, Italy. saviana.barbati@rm.unicatt.it.
authors.forename: Saviana Antonella
authors.initials: SA
authors.lastname: Barbati
authors.affiliation: Department of Neurosurgery, Regina Elena National Cancer Institute, 00144 Rome, Italy. carmine.carapella@ifo.gov.it.
authors.forename: Carmine Maria
authors.initials: CM
authors.lastname: Carapella
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica del Sacro Cuore, 00168 Rome, Italy. claudio.grassi@unicatt.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Grassi
authors.affiliation: Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy. giulia.piaggio@ifo.gov.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: Piaggio
authors.affiliation: Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy. gabriele.toietta@ifo.gov.it.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Toietta
mesh_terms: D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006932:Hyperbilirubinemia / Q000000981:diagnostic imaging*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods*; D008297:Male; D051379:Mice; D008911:Minocycline / Q000494:pharmacology; D061848:Optical Imaging / Q000379:methods*
chemical_list: D000068258:Bevacizumab; D008156:Luciferases; D008911:Minocycline
keywords: bevacizumab; bilirubin; bilirubin-induced neurologic dysfunction; blood–brain barrier; hyperbilirubinemia; in vivo bioluminescence imaging; kernicterus; luciferase; transgenic mice