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.