Bilirubin-induced apoptosis in cultured rat neural cells is aggravated by chenodeoxycholic acid but prevented by ursodeoxycholic acid.

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.

• 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)

Chemical References

• Bile Acids and Salts
• Chenodeoxycholic Acid
• Ursodeoxycholic Acid
• Bilirubin

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)