p38 MAP kinase mediates bilirubin-induced neuronal death of cultured rat cerebellar granule neurons.
Brain damage induced by unconjugated bilirubin, the end product of heme catabolism, in human neonates is a well recognized clinical syndrome. However, the cellular and molecular mechanisms underlying bilirubin neurotoxicity remain unclear. To characterize the sequence of events leading to bilirubin-induced neurotoxicity, we have exposed rat cerebellar granule neurons (CGN) to bilirubin and investigated whether activation of p38 MAP kinase mediates neuronal death. In this study, bilirubin markedly induces an early activation of p38 MAP kinase at 1 h. Pretreatment of neurons with a p38 MAP kinase inhibitor, SB 203580, significantly protected CGN against bilirubin-induced neurotoxicity. Our data suggest that hyperphosphorylation of p38 MAP kinase plays an important role in bilirubin-induced neuronal death and provides a novel approach to discovering drugs to treat bilirubin-induced encephalopathy.
Lin
Suizhen
S
Department of Neurology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
Yan
Chong
C
Wei
Xing
X
Paul
Steven M
SM
Du
Yansheng
Y
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D001663:Bilirubin / Q000494:pharmacology*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D000873:Anthracenes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; C432165:pyrazolanthrone; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D001663:Bilirubin