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Neuromolecular Med. 2006;8(4):513-29.

Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns.

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Division of Newborn Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh, PA, USA.


Kernicterus is a devastating, chronic disabling neurological disorder whose central nervous system (CNS) sequelae reflect both a predilection of bilirubin toxicity for neurons (rather than glial cells) and the regional topography of bilirubin-induced neuronal injury that is characterized by prominent basal ganglia, cochlear, and oculomotor nuclei involvement. The molecular pathogenesis of bilirubin-induced neuronal cell injury, although incompletely understood, likely reflects the untoward effects of hazardous unconjugated bilirubin concentrations on plasma, mitochondrial, and/or endoplasmic reticulum (ER) membranes. These membrane perturbations, in turn, might lead to the genesis of neuronal excitotoxicity, mitochondrial energy failure, or increased intracellular calcium concentration [Ca2+]i. These three phenomena are likely to be linked spatially and temporally in the pathogenesis of bilirubin-induced neuronal injury. Downstream events triggered by increased [Ca2+]i may include, among others, the activation of proteolytic enzymes, apoptotic pathways, and/or necrosis, the individual occurrence of which is likely a function of the degree and duration of bilirubin exposure. A recent study demonstrates the activation of mitogen-activated protein kinase signal transduction pathways by bilirubin heralding a degree of complexity regarding the molecular mechanism(s) of bilirubin-induced neurotoxicity not previously appreciated. There remains, however, a paucity of data regarding specific effects of bilirubin on intracellular signaling and cell death pathways, particularly in vivo. An enhanced understanding of the molecular pathogenesis of bilirubin-induced neuronal injury will lead to the identification of potential novel interventional strategies to protect the CNS against kernicterus.

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