title: Bilirubin and its oxidation products damage brain white matter.
abstract: Brain injury after intracerebral hemorrhage (ICH) occurs in cortex and white matter and may be mediated by blood breakdown products, including hemoglobin and heme. Effects of blood breakdown products, bilirubin and bilirubin oxidation products, have not been widely investigated in adult brain. Here, we first determined the effect of bilirubin and its oxidation products on the structure and function of white matter in vitro using brain slices. Subsequently, we determined whether these compounds have an effect on the structure and function of white matter in vivo. In all, 0.5 mmol/L bilirubin treatment significantly damaged both the function and the structure of myelinated axons but not the unmyelinated axons in brain slices. Toxicity of bilirubin in vitro was prevented by dimethyl sulfoxide. Bilirubin oxidation products (BOXes) may be responsible for the toxicity of bilirubin. In in vivo experiments, unmyelinated axons were found more susceptible to damage from bilirubin injection. These results suggest that unmyelinated axons may have a major role in white-matter damage in vivo. Since bilirubin and BOXes appear in a delayed manner after ICH, preventing their toxic effects may be worth investigating therapeutically. Dimethyl sulfoxide or its structurally related derivatives may have a potential therapeutic value at antagonizing axonal damage after hemorrhagic stroke.
authors.affiliation: 1] Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lakovic
authors.affiliation: Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Jinglu
authors.initials: J
authors.lastname: Ai
authors.affiliation: 1] Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Josephine
authors.initials: J
authors.lastname: D'Abbondanza
authors.affiliation: Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Asma
authors.initials: A
authors.lastname: Tariq
authors.affiliation: 1] Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sabri
authors.affiliation: Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Abdullah K
authors.initials: AK
authors.lastname: Alarfaj
authors.affiliation: Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Punarjot
authors.initials: P
authors.lastname: Vasdev
authors.affiliation: 1] Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada [3] Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert Loch
authors.initials: RL
authors.lastname: Macdonald
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001663:Bilirubin / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D020521:Stroke / Q000378:metabolism* / Q000473:pathology
chemical_list: D001663:Bilirubin