Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading toneurological damage has not been completely elucidated. Innovative strategies of investigation areneeded to more precisely define this pathological process. By longitudinal in vivo bioluminescenceimaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Lucmouse, in which light emission is restricted to the regions of active cell proliferation. We assessedthat acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an incrementin the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive forboth luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation ofmicroglial cells. In addition, we demonstrated that brain induction of bioluminescence was alteredby pharmacological displacement of bilirubin from its albumin binding sites and by modulationof the blood–brain barrier permeability, all pivotal factors in the development of bilirubin-inducedneurologic dysfunction. We also determined that treatment with minocycline, an antibiotic withanti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascularendothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the studysupports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring ofdrugs aiming at preventing acute bilirubin-induced neurological dysfunction.
Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging.
Barbati S A;
2017-01-01
Abstract
Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading toneurological damage has not been completely elucidated. Innovative strategies of investigation areneeded to more precisely define this pathological process. By longitudinal in vivo bioluminescenceimaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Lucmouse, in which light emission is restricted to the regions of active cell proliferation. We assessedthat acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an incrementin the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive forboth luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation ofmicroglial cells. In addition, we demonstrated that brain induction of bioluminescence was alteredby pharmacological displacement of bilirubin from its albumin binding sites and by modulationof the blood–brain barrier permeability, all pivotal factors in the development of bilirubin-inducedneurologic dysfunction. We also determined that treatment with minocycline, an antibiotic withanti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascularendothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the studysupports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring ofdrugs aiming at preventing acute bilirubin-induced neurological dysfunction.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.