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.
Highlights
IntroductionDue to high levels of unconjugated bilirubin, may cause bilirubin encephalopathy, known as kernicterus
Severe hyperbilirubinemia, due to high levels of unconjugated bilirubin, may cause bilirubin encephalopathy, known as kernicterus
Factors which increase UCBFREE, such as hypoalbuminemia, hyperbilirubinemia, and the presence of drugs which displace bilirubin from its binding sites on albumin, as well as blood–brain barrier (BBB) damage, have a clinical relevance in bilirubin-induced neurotoxicity
Summary
Due to high levels of unconjugated bilirubin, may cause bilirubin encephalopathy, known as kernicterus. This condition is characterized by irreversible and selective brain damage or by a broad spectrum of less severe and defined neurologic alterations, referred to as bilirubin-induced neurological dysfunction (BIND) [1,2]. UCBFREE, and not albumin-bound UCB, is able to cross the blood–brain barrier (BBB), and it is, responsible for bilirubin-induced neurotoxicity. Factors which increase UCBFREE, such as hypoalbuminemia, hyperbilirubinemia, and the presence of drugs which displace bilirubin from its binding sites on albumin, as well as BBB damage, have a clinical relevance in bilirubin-induced neurotoxicity. Severe hyperbilirubinemia may induce BBB endothelial disruption [4], possibly exposing the neurons to both UCBFREE and albumin-bound UCB [5]
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