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

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.

• Authors: Ke Lai, Xing-Lei Song, Hao-Song Shi, Xin Qi, Chun-Yan Li, Jia Fang, Fan Wang, Oleksandr Maximyuk, Oleg Krishtal, Tian-Le Xu, Xiao-Yan Li, Kun Ni, Wan-Peng Li, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 530 (02 12 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 32051225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Acid Sensing Ion Channels
• Bilirubin

Topics

• Animals
• Mice
• Acid Sensing Ion Channels
• Bilirubin
• Hyperbilirubinemia, Neonatal (complications)
• Mice, Knockout
• Neurons
• Animals, Newborn
• Disease Models, Animal