Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: An in vitro study

Inês Palmela, Leonor Correia, Rui F M Silva, Hiroyuki Sasaki, Kwang Sik Kim, Dora Brites, Maria A. Brito

Research output: Contribution to journalArticle

Abstract

Ursodeoxycholic acid and its main conjugate glycoursodeoxycholic acid are bile acids with neuroprotective properties. Our previous studies demonstrated their anti-apoptotic, anti-inflammatory and antioxidant properties in neural cells exposed to elevated levels of unconjugated bilirubin as in severe jaundice. In a simplified model of the blood-brain barrier, formed by confluent monolayers of a cell line of human brain microvascular endothelial cells, unconjugated bilirubin has shown to induce caspase-3 activation and cell death, as well as interleukin-6 release and a loss of blood-brain barrier integrity. Here we tested the preventive and restorative effects of these bile acids regarding the disruption of blood-brain barrier properties by unconjugated bilirubin in in vitro conditions mimicking severe neonatal hyperbilirubinemia and using the same experimental blood-brain barrier model. Both bile acids reduced the apoptotic cell death induced by unconjugated bilirubin, but only glycoursodeoxycholic acid significantly counteracted caspase-3 activation. Bile acids also prevented the upregulation of interleukin-6 mRNA, whereas only ursodeoxycholic acid abrogated cytokine release. Regarding barrier integrity, only ursodeoxycholic acid abrogated unconjugated bilirubin-induced barrier permeability. Better protective effects were obtained by bile acid pre-treatment, but a strong efficacy was still observed by their addition after unconjugated bilirubin treatment. Finally, both bile acids showed ability to cross confluent monolayers of human brain microvascular endothelial cells in a time dependent manner. Collectively, data disclose a therapeutic time-window for preventive and restorative effects of ursodeoxycholic acid and glycoursodeoxycholic acid against unconjugated bilirubin-induced blood-brain barrier disruption and damage to human brain microvascular endothelial cells.

Original languageEnglish (US)
Article number80
JournalFrontiers in Neuroscience
Volume9
Issue numberFEB
DOIs
StatePublished - 2015

Fingerprint

Blood-Brain Barrier
Bile Acids and Salts
Bilirubin
Endothelial Cells
Ursodeoxycholic Acid
Caspase 3
Interleukin-6
Brain
Cell Death
Neonatal Hyperbilirubinemia
Jaundice
In Vitro Techniques
Permeability
Anti-Inflammatory Agents
Up-Regulation
Antioxidants
Cytokines
Cell Line
Messenger RNA
glycoursodeoxycholic acid

Keywords

  • Blood-brain barrier
  • Glycoursodeoxycholic acid
  • Human brain microvascular endothelial cells
  • Interleukin-6
  • Unconjugated bilirubin
  • Ursodeoxycholic acid

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin : An in vitro study. / Palmela, Inês; Correia, Leonor; Silva, Rui F M; Sasaki, Hiroyuki; Kim, Kwang Sik; Brites, Dora; Brito, Maria A.

In: Frontiers in Neuroscience, Vol. 9, No. FEB, 80, 2015.

Research output: Contribution to journalArticle

Palmela, Inês ; Correia, Leonor ; Silva, Rui F M ; Sasaki, Hiroyuki ; Kim, Kwang Sik ; Brites, Dora ; Brito, Maria A. / Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin : An in vitro study. In: Frontiers in Neuroscience. 2015 ; Vol. 9, No. FEB.
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T1 - Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin

T2 - An in vitro study

AU - Palmela, Inês

AU - Correia, Leonor

AU - Silva, Rui F M

AU - Sasaki, Hiroyuki

AU - Kim, Kwang Sik

AU - Brites, Dora

AU - Brito, Maria A.

PY - 2015

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AB - Ursodeoxycholic acid and its main conjugate glycoursodeoxycholic acid are bile acids with neuroprotective properties. Our previous studies demonstrated their anti-apoptotic, anti-inflammatory and antioxidant properties in neural cells exposed to elevated levels of unconjugated bilirubin as in severe jaundice. In a simplified model of the blood-brain barrier, formed by confluent monolayers of a cell line of human brain microvascular endothelial cells, unconjugated bilirubin has shown to induce caspase-3 activation and cell death, as well as interleukin-6 release and a loss of blood-brain barrier integrity. Here we tested the preventive and restorative effects of these bile acids regarding the disruption of blood-brain barrier properties by unconjugated bilirubin in in vitro conditions mimicking severe neonatal hyperbilirubinemia and using the same experimental blood-brain barrier model. Both bile acids reduced the apoptotic cell death induced by unconjugated bilirubin, but only glycoursodeoxycholic acid significantly counteracted caspase-3 activation. Bile acids also prevented the upregulation of interleukin-6 mRNA, whereas only ursodeoxycholic acid abrogated cytokine release. Regarding barrier integrity, only ursodeoxycholic acid abrogated unconjugated bilirubin-induced barrier permeability. Better protective effects were obtained by bile acid pre-treatment, but a strong efficacy was still observed by their addition after unconjugated bilirubin treatment. Finally, both bile acids showed ability to cross confluent monolayers of human brain microvascular endothelial cells in a time dependent manner. Collectively, data disclose a therapeutic time-window for preventive and restorative effects of ursodeoxycholic acid and glycoursodeoxycholic acid against unconjugated bilirubin-induced blood-brain barrier disruption and damage to human brain microvascular endothelial cells.

KW - Blood-brain barrier

KW - Glycoursodeoxycholic acid

KW - Human brain microvascular endothelial cells

KW - Interleukin-6

KW - Unconjugated bilirubin

KW - Ursodeoxycholic acid

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