Bilirubin and Brain Toxicity
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AbstractDespite improvements in detection and treatment of neonatal jaundice, there has been an apparent resurgence of bilirubin-induced brain damage. Unresolved issues concerning bilirubin-induced brain damage include the mechanisms by which bilirubin enters the brain and the molecular mechanisms by which bilirubin exerts its toxicity. These issues were the basis for the experimental studies performed in this thesis in pediatrics.
In the first paper (paper I) we hypothesized that treatment with drugs known to inhibit the membrane transport protein phospho-glycoprotein (P-gp) would increase the entry of bilirubin into the brain of young adult Spraque-Dawley rats. In these in vivo experiments brain bilirubin content was examined after the iv injection of a P-gp inhibitor and bilirubin. In the remaining studies (paper II, III and IV) we used human NT2-N neurons to elucidate bilirubin-induced apoptotic and necrotic cell death in vitro. A specific caspase-3 inhibitor (zDEVD.fmk), a general caspase inhibitor (zVAD.fmk) and/or the NMDA receptor antagonist MK-801 were used to further explore the apoptotic cell death pathways involved.
We conclude that drugs known to inhibit P-gp increased the entry of bilirubin into the brain. We speculate whether such drugs may increase the risk of bilirubin-induced brain damage in newborns. Delayed apoptotic cell death predominated over necrotic cell death in human NT2-N neurons after exposure to low and moderate bilirubin concentrations. Both caspase dependent- and NMDA receptor mediated mechanisms, are involved in bilirubin-induced apoptosis. These mechanisms appear to be at least in part distinct, and concurrent inhibition of both pathways with a pancaspase inhibitor and MK-801 provided synergistic protection. Our results should encourage further studies to elucidate the nature of bilirubin-induced apoptosis in vivo.
LIST OF PUBLICATIONS
1. Hankø E, Tommarello S, Watchko JF, Hansen TW. Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain. Pediatric Research 2003; 54:441-445. Artikkel.
2. Hankø E, Hansen TWR, Almaas R, Lindstad J, Rootwelt T. Bilirubin induces apoptosis and necrosis in human NT2-N neurons. Pediatric Research 2005; 57:179-184. Artikkel.
3. Hankø E, Hansen TWR, Almaas R, Paulsen R, Rootwelt T. Synergistic Protection of a General Caspase Inhibitor and MK-801 in Bilirubin-Induced Cell Death in Human NT2-N Neurons. Pediatric Research 2006; 59:72-77. Artikkel.
4. Hankø E, Hansen TWR, Almaas R, Rootwelt T. Recovery after short term bilirubin exposure in human NT2-N neurons. Brain Res. 2006; 1103;1:56-64. Artikkel.