Journal
JOURNAL OF NEUROCHEMISTRY
Volume 112, Issue 1, Pages 56-65Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2009.06429.x
Keywords
bilirubin neurotoxicity; glycolysis; glycoursodeoxycholic acid; mitochondrial dysfunction; oxidative stress; respiratory chain
Categories
Funding
- RENEVAS, Fondo de Investigacion Sanitaria [FIS06/0794]
- Junta de Castilla y Leon
- CONSOLIDER RosasNet [CSD2007-00020, SA066A07]
- Red Terapia Celular-ISCIII
- Fundacao para a Ciencia e a Tecnologia, Lisbon, Portugal [POCI/SAU/MMO/55955/2004, PTDC/SAU-NEU/64385/2006, POCI 2010, BD/30292/2006]
- [SAF2007-61492]
Ask authors/readers for more resources
High levels of unconjugated bilirubin (UCB) may initiate encephalopathy in neonatal life, mainly in pre-mature infants. The molecular mechanisms of this bilirubin-induced neurologic dysfunction (BIND) are not yet clarified and no neuroprotective strategy is currently worldwide accepted. Here, we show that UCB, at conditions mimicking those of hyperbilirubinemic newborns (50 mu M UCB in the presence of 100 mu M human serum albumin), rapidly (within 1 h) inhibited cytochrome c oxidase activity and ascorbate-driven oxygen consumption in 3 days in vitro rat cortical neurons. This was accompanied by a bioenergetic and oxidative crisis, and apoptotic cell death, as judged by the collapse of the inner-mitochondrial membrane potential, increased glycolytic activity, superoxide anion radical production, and ATP release, as well as disruption of glutathione redox status. Furthermore, the antioxidant compound glycoursodeoxycholic acid (GUDCA) fully abrogated UCB-induced cytochrome c oxidase inhibition and significantly prevented oxidative stress, metabolic alterations, and cell demise. These results suggest that the neurotoxicity associated with neonatal bilirubin-induced encephalopathy occur through a dysregulation of energy metabolism, and supports the notion that GUDCA may be useful in the treatment of BIND.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available