Abstract | BACKGROUND/AIMS: Unconjugated bilirubin (UCB) can be neurotoxic in jaundiced neonates and in patients with Crigler-Najjar syndrome. UCB toxicity may culminate in cell death, however, the occurrence of apoptosis has never been investigated. Ursodeoxycholic acid (UDCA) is a strong modulator of the apoptotic threshold in both hepatic and nonhepatic cells. The aims of this study were to determine whether apoptosis plays a role in neural cell death induced by UCB, and to investigate the ability of UDCA to prevent cell death. METHODS: Cultured rat astrocytes were incubated with UCB (17 and 86 microM) plus albumin (5.7 and 28.7 microM) for 4-22 h. In addition, astrocytes and neurones were treated with either UCB, 50 microM UDCA, or their combination for 4 h. Cultures were scored for nonviable cells by trypan blue dye exclusion. Apoptosis was assessed by Hoechst staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling assay. RESULTS: UCB induced a concentration- and time-dependent decrease in astrocyte viability. Apoptosis was 4- and 7-fold increased after 4 h exposure to 17 and 86 microM UCB, respectively (P < 0.01). UDCA reduced apoptosis to <7%, which represents a appoximately 60% protection (P < 0.01). Cholic acid was not protective, and chenodeoxyholic acid aggravated UCB toxicity (P < 0.05). Finally, neurones showed a 1.5-fold greater sensitivity than astrocytes to UCB, while UDCA was still protective. CONCLUSIONS: UCB is toxic to both astrocytes and neurones, causing cell death through an apoptotic process. Moreover, UDCA inhibits UCB-induced apoptosis in neural cells and this could not be mimicked by other bile acids.
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Authors | R F Silva, C M Rodrigues, D Brites |
Journal | Journal of hepatology
(J Hepatol)
Vol. 34
Issue 3
Pg. 402-8
(Mar 2001)
ISSN: 0168-8278 [Print] Netherlands |
PMID | 11322201
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Bile Acids and Salts
- Chenodeoxycholic Acid
- Ursodeoxycholic Acid
- Bilirubin
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Topics |
- Animals
- Apoptosis
(drug effects)
- Astrocytes
(drug effects, physiology)
- Bile Acids and Salts
(physiology)
- Bilirubin
(pharmacology, poisoning)
- Cells, Cultured
- Chenodeoxycholic Acid
(pharmacology)
- Neurons
(drug effects, physiology)
- Rats
- Rats, Wistar
- Ursodeoxycholic Acid
(pharmacology)
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