Alterations of Blood Brain Barrier Function in Hyperammonemia: An Overview

Marta Skowron ska 0 Jan Albrecht 0 0 M. Skowronska J. Albrecht (&) Departament of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences , 02-106 Warszawa, Pawinskiego 5, Poland Ammonia is a neurotoxin involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy, a condition associated with acute(ALF) or chronic liver failure. This article reviews evidence that apart from directly affecting the metabolism and function of the central nervous system cells, ammonia influences the passage of different molecules across the blood brain barrier (BBB). A brief description is provided of the tight junctions, which couple adjacent cerebral capillary endothelial cells to each other to form the barrier. Ammonia modulates the transcellular passage of low-to medium-size molecules, by affecting their carriers located at the BBB. Ammonia induces interrelated aberrations of the transport of the large neutral amino acids and aromatic amino acids (AAA), whose influx is augmented by exchange with glutamine produced in the course of ammonia detoxification, and maybe also modulated by the extracellularly acting gamma-glutamyl moiety transferring enzyme, gammaglutamyl-transpeptidase. Impaired AAA transport affects neurotransmission by altering intracerebral synthesis of catecholamines (serotonin and dopamine), and producing ''false neurotransmitters'' (octopamine and phenylethylamine). Ammonia also modulates BBB transport of the cationic amino acids: the nitric oxide precursor, arginine, and ornithine, which is an ammonia trap, and affects the transport of energy metabolites glucose and creatine. - Moreover, ammonia acting either directly or in synergy with liver injury-derived inflammatory cytokines also evokes subtle increases of the transcellular passage of molecules of different size (BBB leakage), which appears to be responsible for the vasogenic component of cerebral edema associated with ALF. Homeostasis of the brain is maintained owing to its rigidly controlled communication with the peripheral tissues. Entry of metabolites from the periphery to the brain is controlled by the blood brain barrier (BBB). The major structural constituents of the BBB are the cerebral microvascular endothelial cells, and their barrier function relies on so- called tight-junctions (TJs), consisting of transmembrane components: junctional adhesion molecule (JAM)-1, occludin, and the claudins and intracellular proteins: ZO-1, ZO-2, and ZO-3, which link transmembrane proteins to the actin filaments of cytoskeleton and in this way improve stability and functioning of the TJ. Adherent junctions which are located in the basal region below the TJs, also contribute to the barrier function. Cadherins stabilize adhesion between neighboring endothelial cells, while intracellularly, catenins link cadherins to the cytoskeleton (Fig. 1). The BBB is both physical and metabolic in its nature. Physically, the TJs limit free paracellular diffusion of low molecular weight compounds and make the transcellular transport of larger molecules dependent on specific transport systems, which can be grouped Fig. 1 Composition of the tight junction and adherence junction which collectively restrict the paracellular passage of solutes across the BBB accordingly to the class of molecules transported (Hawkins and Davis 2005; Carvey et al. 2009). These transport systems are located in endothelial cells, and are modulated both intrinsically and by other cells of the neurovascular unit: astrocytes and pericytes (Simard and Nedergaard 2004). Fine-tuning of the transport involves its polarization by differential location of the transport systems in the luminal versus abluminal membranes, which holds in particular for the different amino acid transport systems (Hawkins et al. 2006). In this way two ultimate and complementary goals are reached: (i) control of the inflow and outflow of metabolic precursors and products, (ii) prevention of entry to the brain of undesired compounds. The sections below describes the evolution of views on the role of BBB changes in the pathogenesis of diseases associated with increased exposure of the brain to bloodderived ammonia. Studies on BBB penetration by different compounds in HE models: a historical account section gives a historical perspective on the experimental studies on ammonia- and HE-induced changes in BBB penetration of different compounds, without emphasis on the underlying mechanisms. Transcellular passage of different molecules across the endothelium: roles of active transport section of the review will elaborate on the relatively well explored subject of modulation of transcellular passage, which represents active transport of medium- to large-molecules, and channel- or transporter-mediated ion fluxes across the capillary endothelial cell membranes. BBB leakage induced by ammonia and inflammatory molecules: new vistas on the underlying mechanisms section is devoted to the new findings regarding the mechanisms underlying alterations in the paracellular transport which is defined as BBB leakage, the role of which in ammonia neurotoxicity has so far been underestimated. Studies on BBB Penetration by Different Compounds in HE Models: A Historical Account Pioneering studies pertinent to the effect of ammonia on BBB permeability were performed on animals with portacaval anastomosis (PCA)a model which mimics the condition of portal-systemic shunting in patients with liver cirrhosis. Laursen et al. (1975) showed that BBB in PCA rats is leaky to horseradish peroxidase (HRP). This observation has been confirmed by Sumner (1982) in a similar experimental setting, and by others using different BBB permeability markers and/or HE models: by Zaki (1983) also in PCA rats who measured amino acid influx using the Oldendorf perfusion technique (Oldendorf 1971), and by Horowitz et al. (1983) in galactosamine-induced animal model of acute liver failure (ALF), where permeability changes to aaminoisobutyric acid were measured. However, other contemporary animal studies often performed in similar HE models and using similar markers, revealed no brain vascular permeability changes. Examples include the absence of changes of sucrose and methylaminoisobutyric acid permeation in galactosamine induced HE (Lo et al. 1987), and to mannitol or ions in the PCA model (Sarna et al. 1977; Alexander et al. 2000). As will be discussed in Transcellular passage of different molecules across the endothelium: roles of active transport and BBB leakage induced by ammonia and inflammatory molecules: new vistas on the underlying mechanisms sections, controversies about the BBB status as assessed with different compounds have lasted until the present time, with BBB changes being either confirmed (Wang et al. 2011) or denied (Goldbecker et al. 2010). Incoherent results were also obtained with regard to the passage of ammonia through the BBB, as monito (...truncated)