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: Isabella Manni, Giuliana Di Rocco, Salvatore Fusco, Lucia Leone, Saviana Antonella Barbati, Carmine Maria Carapella, Claudio Grassi, Giulia Piaggio, Gabriele Toietta
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 18 Issue 1 (Dec 28 2016) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 28036021 (Publication Type: Journal Article)

Chemical References

• Bevacizumab
• Luciferases
• Minocycline

Topics

• Animals
• Bevacizumab (pharmacology)
• Blood-Brain Barrier (diagnostic imaging, drug effects, metabolism)
• Female
• Hyperbilirubinemia (diagnostic imaging)
• Luciferases (genetics, metabolism)
• Luminescent Measurements (methods)
• Male
• Mice
• Minocycline (pharmacology)
• Optical Imaging (methods)