Format

Send to

Choose Destination
Cell Chem Biol. 2019 Jul 23. pii: S2451-9456(19)30218-1. doi: 10.1016/j.chembiol.2019.07.006. [Epub ahead of print]

Bilirubin Links Heme Metabolism to Neuroprotection by Scavenging Superoxide.

Author information

1
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
3
Duke University School of Medicine, Durham, NC 27701, USA.
4
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: bpaul8@jhmi.edu.
9
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: ssnyder1@jhmi.edu.

Abstract

Bilirubin is one of the most frequently measured metabolites in medicine, yet its physiologic roles remain unclear. Bilirubin can act as an antioxidant in vitro, but whether its redox activity is physiologically relevant is unclear because many other antioxidants are far more abundant in vivo. Here, we report that depleting endogenous bilirubin renders mice hypersensitive to oxidative stress. We find that mice lacking bilirubin are particularly vulnerable to superoxide (O2⋅-) over other tested reactive oxidants and electrophiles. Whereas major antioxidants such as glutathione and cysteine exhibit little to no reactivity toward O2⋅-, bilirubin readily scavenges O2⋅-. We find that bilirubin's redox activity is particularly important in the brain, where it prevents excitotoxicity and neuronal death by scavenging O2⋅- during NMDA neurotransmission. Bilirubin's unique redox activity toward O2⋅- may underlie a prominent physiologic role despite being significantly less abundant than other endogenous and exogenous antioxidants.

KEYWORDS:

NMDA receptor; bilirubin; biliverdin; heme; metabolism; neuroprotection; oxidative stress; superoxide

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center