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Bilirubin selectively inhibits cytochrome c oxidase activity and induces apoptosis in immature cortical neurons: assessment of the protective effects of glycoursodeoxycholic acid
Author(s) -
Vaz Ana Rita,
DelgadoEsteban Maria,
Brito Maria Alexandra,
Bolaños Juan P.,
Brites Dora,
Almeida Angeles
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06429.x
Subject(s) - neuroprotection , neurotoxicity , cytochrome c oxidase , oxidative stress , glutathione , cytochrome c , programmed cell death , bilirubin , biochemistry , mitochondrion , chemistry , superoxide , apoptosis , pharmacology , medicine , biology , endocrinology , toxicity , enzyme
J. Neurochem. (2010) 112 , 56–65. Abstract 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 μM UCB in the presence of 100 μM 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.