Unconjugated bilirubin differentially affects the redox status of neuronal and astroglial cells.
We investigated whether nerve cell damage by unconjugated bilirubin (UCB) is mediated by oxidative stress and ascertained the neuronal and astroglial susceptibility to injury. Several oxidative stress biomarkers and cell death were determined following incubation of neurons and astrocytes isolated from rat cortical cerebrum with UCB (0.01-1.0 microM). We show that UCB induces a dose-dependent increase in neuronal death in parallel with the oxidation of cell components and a decrease in the intracellular glutathione content. Comparison of the results obtained in both cell types demonstrates that neurons are more vulnerable than astrocytes to oxidative injury by UCB, for which accounts the lower glutathione stores in neuronal cells. Moreover, neuronal oxidative injury is prevented by supplementation with N-acetylcysteine, a glutathione precursor, whereas astroglial sensitivity to UCB is enhanced by inhibition of glutathione synthesis, using buthionine sulfoximine. Collectively, we demonstrate that oxidative stress is involved in UCB neurotoxicity and depict a new therapeutic approach for UCB-induced oxidative damage.
Brito
Maria A
MA
Centro de Patogénese Molecular - Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. abrito@ff.ul.pt
Rosa
Alexandra I
AI
Falcão
Ana S
AS
Fernandes
Adelaide
A
Silva
Rui F M
RF
Butterfield
D Allan
DA
Brites
Dora
D
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects*; D001663:Bilirubin / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010084:Oxidation-Reduction / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D001663:Bilirubin; D000111:Acetylcysteine