Bilirubin and its Oxidation Products Damage Brain White Matter

• Published in: Journal of cerebral blood flow and metabolism Vol. 34; no. 11; pp. 1837 - 1847
• Main Authors: Lakovic, Katarina, Ai, Jinglu, D'Abbondanza, Josephine, Tariq, Asma, Sabri, Mohammed, Alarfaj, Abdullah K, Vasdev, Punarjot, Macdonald, Robert Loch
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.11.2014; Sage Publications Ltd; Nature Publishing Group
• Subjects: Animals; Axons - metabolism; Axons - pathology; Bilirubin - metabolism; Brain Injuries - metabolism; Brain Injuries - pathology; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cerebral Hemorrhage - metabolism; Cerebral Hemorrhage - pathology; Male; Mice; Original; Oxidation-Reduction; Stroke - metabolism; Stroke - pathology; intracerebral hemorrhage; white matter; bilirubin toxicity; mice
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2014.154

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.