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 (UCB) 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, UCB 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 UCB 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 UCB, 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 UCB-induced barrier permeability. Better protective effects were obtained by bile acid pre-treatment, but a strong efficacy was still observed by their addition after UCB 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 UCB-induced blood-brain barrier disruption and damage to human brain microvascular endothelial cells.
Highlights
In neonatal life, increased levels and prolonged exposure to unconjugated bilirubin (UCB) may trigger bilirubin-induced neurological dysfunction (Cohen et al, 2010)
ursodeoxycholic acid (UDCA) and glycoursodeoxycholic acid (GUDCA) Protect human brain microvascular endothelial cells (BMEC) (HBMEC) from UCB-Induced Apoptosis, but only GUDCA is Effective in Reducing Caspase-3 Activation UCB-induced apoptosis in the HBMEC line includes the presence of apoptotic features that increased with the time of exposure and reached maximal levels at 48 h (Palmela et al, 2011)
This time was chosen to evaluate the ability of UDCA and GUDCA to protect HBMEC from UCB-induced apoptosis
Summary
In neonatal life, increased levels and prolonged exposure to unconjugated bilirubin (UCB) may trigger bilirubin-induced neurological dysfunction (Cohen et al, 2010). UCB-induced disruption of barrier properties of BMEC was observed even in the presence of astrocytes (Cardoso et al, 2012), an in vitro co-culture model that better resembles the in vivo condition These in vitro evidences have been confirmed in autopsy studies of a kernicterus premature infant presenting increased vascularization and infiltration of erythrocytes and albumin in the brain parenchyma (Brito et al, 2013). Recent studies of additional cases of kernicterus have shown that the most susceptible brain regions to UCB toxicity, as the cerebellum, hippocampus, and basal ganglia, present marked signs of BBB dysfunction, as reduced pericyte vascular coverage and alterations in the basement membrane (Palmela et al, submitted) These features point to an enhanced permeability of the vascular walls, at least in severely ill pre-term infants with bilirubin encephalopathy
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