Research ArticleNEONATAL JAUNDICE

Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice

See allHide authors and affiliations

Science Translational Medicine  12 Feb 2020:
Vol. 12, Issue 530, eaax1337
DOI: 10.1126/scitranslmed.aax1337

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Targeting acidity in jaundice

Neonatal hyperbilirubinemia, also called jaundice, is a pediatric condition caused by high bilirubin levels. When associated with acidosis, jaundice can trigger neurotoxicity and lead to neurological impairments. Now, Lai et al. investigated the link between acidosis and jaundice in human samples and animal models. In samples from children with concomitant acidosis and jaundice, neuronal injury was increased compared with children with jaundice and no acidosis. In mice, bilirubin potentiated the activity of acid-sensing ion channels (ASICs) in neurons, increased firing, and caused cell death. Hyperbilirubinemia and acidosis promoted cognitive impairments in mice that were prevented by ASIC deletion. Targeting ASICs might reduce neurological impairments associated with jaundice.

Abstract

Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory and complex sensorimotor functions in vivo, which are largely attenuated in ASIC1a null mice. These findings suggest that targeting acidosis and ASICs may attenuate neonatal hyperbilirubinemia complications.

View Full Text

Stay Connected to Science Translational Medicine


Editor's Blog