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

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.

Testicular immunohistochemical and Ultrastructural changes associated with chronic cholestasis in rats: Effect of ursodeoxycholic acid

“…Previous studies have reported that hydrophobic bile acids contribute to the breakdown of the blood brain barrier seen during cholestasis via the disruption of tight junctions [28,29]. Alteration of tight junction structure was also observed in cells exposed to toxic bile acids [30,31].…”

“…UDCA prevents mitochondrial perturbation and consequential mitochondrial swelling [69,86], which are ultrastructural changes commonly observed in cells exposed to toxic bile acids [87][88][89]. Another advantage of UDCA is its ability to cross the blood barrier and prevent changes in its integrity [29].…”

Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System

“…There are reports that both unconjugated and conjugated bile acids can cross the BBB (Keene et al, 2001 ; Palmela et al, 2015 ; McMillin et al, 2016 ; Figure 3A ), however, the involved mechanisms are still uncertain. Unconjugated bile acids might diffuse across the BBB, because CA, CDCA, and deoxycholic acid (DCA) are capable of diffusing across phospholipid bilayers (Kamp and Hamilton, 1993 ) and their brain levels correlate with their serum levels (Higashi et al, 2017 ).…”

“…Consequently, allowing bile acids and other molecules to diffuse into the brain. UDCA and its glycine-conjugated form glyco-ursodeoxycholic acid (GUDCA) exert a protective effect on brain endothelial cells by reducing apoptosis (Palmela et al, 2015 ). In addition, a recent study showed that microglial cells express TGR5 and that binding of taurine-conjugated UDCA (TUDCA) to TGR5 has anti-inflammatory effects in a mouse model of acute brain inflammation (Yanguas-Casás et al, 2017 ).…”

Bile Acid Signaling and Cardioprotection

“…Apart from liver, UDCA is also reported to have anti-apoptotic effect in other cells such as, cholangiocytes [93], brain [94], eyes [95] pro-inflammatory cytokines compared to non-alcoholic drinker of cirrhotic patients who have high level of unconjugated UDCA [5]. A clinical trial conducted on cystic fibrosis patients reported that UDCA protects patients' liver and improves liver function test without affecting their lung function [98].…”