Alterations of Blood Brain Barrier Function in Hyperammonemia: An Overview

Abstract

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, gamma-glutamyl-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.

The Gut Microbiome and the Brain

“…61 In addition to direct neurotoxic injury, ammonia alters function of the blood-brain barrier, impairing intracerebral synthesis of serotonin and dopamine and producing abnormal neurotransmitters such as octopamine. 73 Minimal HE (MHE) is a common neurocognitive disorder that occurs in 80% of cirrhotic patients 74 and often evades diagnosis. 75 It is characterized by subtle intellectual deficits and psychomotor abnormalities that have a significant negative impact on health-related quality of life, impair motor vehicle operation, and increase the incidence of vehicular accidents.…”

Behavioral alterations and Fos protein immunoreactivity in brain regions of bile duct-ligated cirrhotic rats

“…A key role for ammonia in the pathogenesis of HE has been extensively supported by both clinical and experimental data (Gerber and Schomerus 2000, Vaquero et al 2003, Jover et al 2006, Khungar and Poordad, 2012. Ammonia crosses the blood-brain barrier mainly through the transendothelial route, using potassium channels and transporters or by replacing other cations with comparable hydrated radius (for a review see Skowrońska and Albrecht 2012). In the brain, the synthesis of glutamate is linked to a substrate cycle involving glutamine metabolism (Bak et al 2006) in neurons and astrocytes.…”

Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

“…The content of the latter in the brain tissue is significantly increased, which is due to the synthesis of glutamine during the detoxification of ammonia. Increased intake of aromatic amino acids leads to violations of catecholamine production (serotonin and dopamine) and instead false neurotransmitters (octopamine and phenylethylamine) synthesis, which can deteriorate the serotoninergic, GABA-ergic and glutamate-ergic neurotransmission [36]. The total amount of most experimental investigations on animals HE models describe malfunctions of 4 neurotransmitter systems in the brain: GABA-benzodiazepin-ergic, dopaminergic, serotoninergic and glutamate-ergic [1].…”

“…This opinion was disproved by studies showing an increase extraction of ammonia from the blood by brain tissue in HE but to date this issue is still open [50]. The functions of the endothelium and the BBB tightness can be altered by a variety of substances, including ammonia, interleukins, NO, adenosine, purine nucleotides, steroid hormones, serotonin, bradykinin [36]. The high selectivity of the BBB permeability is due to the presence of tight junctions (TJ) between capillary endothelial cells, weakly expressed pinocytosis transport and thickened basement membrane.…”