Abstract
Liver failure is often associated with hepatic encephalopathy, due to dyshomeostasis of the central nervous system (CNS). Under physiological conditions, the CNS homeostasis is precisely regulated by the blood-brain barrier (BBB). The BBB consists of brain microvessel endothelial cells connected with a junctional complex by the adherens junctions and tight junctions. Its main function is to maintain brain homoeostasis via limiting the entry of drugs/toxins to brain. The brain microvessel endothelial cells are characterized by minimal pinocytotic activity, absent fenestrations, and highly expressions of ATP-binding cassette (ABC) family transporters (such as P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated proteins). These ABC transporters prevent brain from toxin accumulation by pumping toxins out of brain. Accumulating evidences demonstrates that liver failure diseases altered the expression and function of ABC transporters at The BBB, indicating that the alterations subsequently affect drugs’ brain distribution and CNS activity/neurotoxicity. ABC transporters also mediate the transport of endogenous substrates across the BBB, inferring that ABC transporters are also implicated in some physiological processes and the development of hepatic encephalopathy. This paper focuses on the alteration in the BBB permeability, the expression and function of ABC transporters at the BBB under liver failure status and their clinical significances.
Highlights
Liver failure is often associated with hepatic encephalopathy, due to accumulation of neurotoxins in brain
ATP-binding cassette (ABC) transporters expressed at brain include P-glycoprotein (P-GP/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug associated resistance proteins (MRPs/ABCCs)
reactive oxygen species (ROS) scavenger N-acetylcysteine and extracellular-regulated protein kinase 1/2 (ERK1/2) inhibitor U0126 restored the alterations by ammonia and H2O2. These results indicated that acute liver failure (ALF) down-regulated the expression and function of brain that BCRP is partly via ammonia-ROS-ERK1/2 pathway [53]
Summary
Liver failure is often associated with hepatic encephalopathy, due to accumulation of neurotoxins in brain. Tight junctions consist of multiple proteins, and include junctional adhesion molecules(JAMs), occludin, claudins (such as claudin-1, claudin-3, and claudin-5), and zonulla occluden proteins (such as ZO-1, ZO-2 and ZO-3) [2] They form the primary physical barrier component of the BBB, and their function is to restrict paracellular entry of various endogenous and exogenous substances—leading to higher transendothelial electrical resistance (1500~2000 Ωcm2) across the BBB compared with that (i.e., 3–33 Ωcm2) in other vascular tissues [1,2]. Disruption of the extracellular matrix was reported to be associated with the loss of the BBB function and the increases in BBB permeability [2] Both brain microvessel endothelial cells and associated astrocyte processes are distinctly connected with noradrenergic, serotonergic, cholinergic and GABAergic neurons, demonstrating that BBB function is probably regulated by these neurons. These results indicate that quinolinic acid is involved in pathogenesis of hepatic encephalopathy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
