TY - JOUR
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 S.
AU - Brites, Dora
AU - Brito, Maria A.
N1 - Publisher Copyright:
© 2015 Palmela, Correia, Silva, Sasaki, Kim, Brites and Brito.
PY - 2015
Y1 - 2015
N2 - 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.
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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U2 - 10.3389/fnins.2015.00080
DO - 10.3389/fnins.2015.00080
M3 - Article
C2 - 25821432
AN - SCOPUS:84924347868
SN - 1662-4548
VL - 9
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
IS - FEB
M1 - 80
ER -