• Ammonia
• Astrocyte
• Edema
• Glutamine
• Hepatic encephalopathy
• Microglia
• Neuroinflammation
• Neurotransmission

• Hepatic Encephalopathy/pathology
• Hepatic Encephalopathy/metabolism
• Humans
• Neuroglia/pathology
• Neuroglia/metabolism
• Animals
• Astrocytes/pathology
• Astrocytes/metabolism

Ammonia toxicity in the brain primarily affects astrocytes via a mechanism in which oxidative stress (OS), is coupled to the imbalance between glutamatergic and GABAergic transmission. Ammonia also downregulates the astrocytic N system transporter SN1 that controls glutamine supply from astrocytes to neurons for the replenishment of both neurotransmitters. Here, we tested the hypothesis that activation of Nrf2 is the process that links ammonia-induced OS formation in astrocytes to downregulation and inactivation of SN1 and that it may involve the formation of a complex between Nrf2 and Sp1. Treatment of cultured cortical mouse astrocytes with ammonia (5 mM NH₄Cl for 24 h) evoked Nrf2 nuclear translocation, increased its activity in a p38 MAPK pathway-dependent manner, and enhanced Nrf2 binding to Slc38a3 promoter. Nrf2 silencing increased SN1 mRNA and protein level without influencing astrocytic [³H]glutamine transport. Ammonia decreased SN1 expression in Nrf2 siRNA treated astrocytes and reduced [³H]glutamine uptake. In addition, while Nrf2 formed a complex with Sp1 in ammonia-treated astrocytes less efficiently than in control cells, treatment of astrocytes with hybrid-mode inactivated Sp1-Nrf2 complex (Nrf2 silencing + pharmacological inhibition of Sp1) did not affect SN1 protein level in ammonia-treated astrocytes. In summary, the results document that SN1 transporter dysregulation by ammonia in astrocytes involves activation of Nrf2 but does not require the formation of the Sp1-Nrf2 complex.

• Nrf2
• SN1 (SNAT3)
• Sp1
• astrocytes
• glutamine
• glutamine transport

• Amino Acid Transport Systems, Neutral/genetics
• Amino Acid Transport Systems, Neutral/metabolism
• Ammonia/toxicity
• Animals
• Astrocytes/drug effects
• Astrocytes/metabolism
• Astrocytes/pathology
• Cerebral Cortex/drug effects
• Cerebral Cortex/metabolism
• Cerebral Cortex/pathology
• Gene Expression Regulation/drug effects
• Mice
• Mice, Inbred C57BL
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Sp1 Transcription Factor/genetics
• Sp1 Transcription Factor/metabolism

• TCA cycle
• autophagy
• glutamine metabolism
• hepatic encephalopathy
• hyperammonemia
• mitochondrial dysfunction

• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/pathology
• Astrocytes/metabolism
• Hyperammonemia/metabolism
• Hyperammonemia/pathology
• Humans
• Energy Metabolism
• Animals
• Glutamate Dehydrogenase/metabolism
• Ammonia/metabolism

• MR spectroscopy
• astrocytes
• neurophysiology
• oscillatory activity
• osmotic and oxidative stress
• transcranial magnetic stimulation

• Hepatic Encephalopathy/metabolism
• Humans
• Animals
• Ammonia/metabolism
• Oxidative Stress

• Brain energy metabolism
• Glutamate dehydrogenase
• Hepatic encephalopathy
• Hyperammonemia
• Mitochondria
• TCA cycle

• Amination
• Amino Acids/metabolism
• Ammonia/pharmacology
• Astrocytes/drug effects
• Astrocytes/metabolism
• Cell Line, Tumor
• Cell Respiration/drug effects
• Citric Acid Cycle/drug effects
• Energy Metabolism/drug effects
• Glutamate Dehydrogenase/metabolism
• Glycolysis/drug effects
• Humans
• Hydrogen-Ion Concentration
• Hyperammonemia/metabolism
• Ketoglutaric Acids/metabolism
• Metabolome/drug effects
• Metabolomics
• Mitochondria/drug effects
• Mitochondria/metabolism
• Mitochondrial Proteins/metabolism
• Models, Biological
• Sirtuins/metabolism

• Deutsche Forschungsgemeinschaft
• Heinrich-Heine-Universität Düsseldorf

• Ammonia
• Astrocyte swelling
• Cytotoxic edema
• Hepatic encephalopathy
• Liver failure

• Ammonia/metabolism
• Astrocytes/metabolism
• Astrocytes/pathology
• Brain/metabolism
• Brain/pathology
• Brain Edema/metabolism
• Brain Edema/pathology
• Cell Size
• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/pathology
• Humans
• Hyperammonemia/metabolism
• Hyperammonemia/pathology
• Oxidative Stress/physiology

Acute liver failure (ALF) implies a severe and rapid liver dysfunction that leads to impaired liver metabolism and hepatic encephalopathy (HE). Recent studies have suggested that several brain alterations such as astrocytic dysfunction and energy metabolism impairment may synergistically interact, playing a role in the development of HE. The purpose of the present study is to investigate early alterations in redox status, energy metabolism and astrocytic reactivity of rats submitted to ALF. Adult male Wistar rats were submitted either to subtotal hepatectomy (92% of liver mass) or sham operation to induce ALF. Twenty-four hours after the surgery, animals with ALF presented higher plasmatic levels of ammonia, lactate, ALT and AST and lower levels of glucose than the animals in the sham group. Animals with ALF presented several astrocytic morphological alterations indicating astrocytic reactivity. The ALF group also presented higher mitochondrial oxygen consumption, higher enzymatic activity and higher ATP levels in the brain (frontoparietal cortex). Moreover, ALF induced an increase in glutamate oxidation concomitant with a decrease in glucose and lactate oxidation. The increase in brain energy metabolism caused by astrocytic reactivity resulted in augmented levels of reactive oxygen species (ROS) and Poly [ADP-ribose] polymerase 1 (PARP1) and a decreased activity of the enzymes superoxide dismutase and glutathione peroxidase (GSH-Px). These findings suggest that in the early stages of ALF the brain presents a hypermetabolic state, oxidative stress and astrocytic reactivity, which could be in part sustained by an increase in mitochondrial oxidation of glutamate.

• acute liver failure
• brain energy metabolism
• glial reactivity
• hepatic encephalopathy
• mitochondria
• redox homeostasis

• Ferrous iron
• Glucosamine
• Glutamine
• RNA oxidation
• Senescence

Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients.

Using primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an in vivo rat HE model, and post mortem brain samples of liver cirrhosis patients with HE we analyzed whether and how hyperammonemia modulates autophagy.

We show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an in vivo rat HE model. Transglutaminase 2 (TGM2), a factor promoting autophagy, is upregulated in astrocytes of in vitro- and in vivo-HE models as well as in post mortem brain samples of liver cirrhosis patients with HE, but not in patients without HE. LC3, a commonly used autophagy marker, is significantly increased in the brain of HE patients. Ammonia also modulated autophagy moderately in neuronal cells. We show that taurine, known to ameliorate several parameters caused by hyperammonemia in patients suffering from liver failure, is highly potent in reducing ammonia-induced impairment of autophagic flux. This protective effect of taurine is apparently not linked to inhibition of mTOR signaling but rather to reducing ammonia-induced ROS formation.

Our data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE.

Supported by the DFG, CRC974 “Communication and Systems Relevance in Liver Injury and Regeneration“, Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).

• Autophagy
• Hepatic encephalopathy
• Liver disease
• Lysosome
• Taurine

• Animals
• Astrocytes/metabolism
• Astrocytes/ultrastructure
• Autophagy
• Autopsy
• Biopsy
• Cell Line
• Cells, Cultured
• Hepatic Encephalopathy/complications
• Hepatic Encephalopathy/etiology
• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/pathology
• Humans
• Hydrogen-Ion Concentration
• Hyperammonemia/etiology
• Lysosomes/metabolism
• Lysosomes/ultrastructure
• Mice
• Neurons/metabolism
• Neurons/ultrastructure
• Protein Glutamine gamma Glutamyltransferase 2
• Rats
• Reactive Oxygen Species/metabolism

• R28 AA012725 NIAAA NIH HHS

The involvement of the astrocytic SN1 (SNAT3) transporter in ammonia-induced l-glutamine retention was recently documented in mouse-cultured astrocytes. Here we investigated the involvement of specificity protein 1 (Sp1) transcription factor in SN1 regulation in ammonium chloride (“ammonia”)-treated astrocytes. Sp1 expression and its cellular localization were determined using real-time qPCR, Western blot, and confocal microscopy. Sp1 binding to Snat3 promoter was analyzed by chromatin immunoprecipitation. The role of Sp1 in SN1 expression and SN1-mediated [³H]glutamine uptake in ammonia-treated astrocytes was verified using siRNA and mithramycin A. The involvement of protein kinase C (PKC) isoforms in Sp1 level/phosphorylation status was verified using siRNA technology. Sp1 translocation to the nuclei and its enhanced binding to the Snat3 promoter, along with Sp1 dependence of system N-mediated [³H]glutamine uptake, were observed in astrocytes upon ammonia exposure. Ammonia decreased the level of phosphorylated Sp1, and the effect was reinforced by long-term incubation with PKC modulator, phorbol 12-myristate 13-acetate, which is a treatment likely to dephosphorylate Sp1. Furthermore, silencing of the PKCδ isoform appears to enhance the ammonia effect on the Sp1 level. Collectively, the results demonstrate the regulatory role of Sp1 in regulation of SN1 expression and activity in ammonia-treated astrocytes and implicate altered Sp1 phosphorylation status in this capacity.

• SN1 (SNAT3), Sp1
• ammonia
• astrocytes
• glutamine
• protein kinase C

• Hyperammonaemia
• Liver injury
• MAPK
• NF-κB
• TLR5

• ARE, Antioxidant Response Elements
• BDNF, Brain-Derived Neurotrophic Factor
• Eph, Ephrine
• EphR, Ephrine Receptor
• GADD45α, Growth Arrest and DNA Damage Inducible 45α
• GS, Glutamine Synthetase
• HE, Hepatic Encephalopathy
• HO1, Heme Oxygenase 1
• LOLA, l-Ornithine-l-Aspartate
• MAP, Mitogen Activated Protein Kinases
• NAPDH, Reduced Form of Nicotinamide Adenine Dinucleotide Phosphate
• Nox, NADPH Oxidase
• Nrf2, Nuclear Factor-Like 2
• PBR, Peripheral-Type Benzodiazepine Receptor
• PTN, Protein Tyrosine Nitration
• RNOS, Reactive Nitrogen and Oxygen Species
• ROS, Reactive Oxygen Species
• SA-β-Gal, Senescence-Associated β-d-Galactosidase
• TSP, Trombospondin
• TrkBT, Truncated Tyrosine Receptor Kinase B
• ZnPP, Zinc Protoporphyrin
• ammonia
• astrocytes
• heme oxygenase 1
• hepatic encephalopathy
• mPT, Mitochondrial Permeability Transition
• miRNAs
• nNOS, Neuronal-Type Nitric-Oxide Synthase
• oxidative stress

• Ammonia
• Carbon monoxide
• Cytoprotection
• Endothelial cells
• Heme oxygenase-1

• Acetylcysteine/administration & dosage
• Ammonia/administration & dosage
• Ammonia/metabolism
• Ammonium Chloride/administration & dosage
• Animals
• Arteries/drug effects
• Arteries/metabolism
• Carbon Monoxide/administration & dosage
• Cell Survival/drug effects
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Gene Expression Regulation/drug effects
• Heme Oxygenase-1/biosynthesis
• Heme Oxygenase-1/genetics
• Humans
• Mice
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Promoter Regions, Genetic/genetics
• Reactive Oxygen Species/metabolism
• Rotenone/administration & dosage
• Signal Transduction/drug effects
• Tumor Necrosis Factor-alpha/genetics

• 15GRNT25250015 American Heart Association-American Stroke Association
• R01 HL059976 NHLBI NIH HHS

Acute liver damage may be followed by biochemical, behavioral, and pathological alterations, which can result in serious complications and even death.

In this experimental study we determined whether coenzyme Q10 (CoQ10), a common supplementary medicine known to have protective, antioxidative, and anti-inflammatory effects in cells, has any protective effect against thioacetamide (TAA)-induced liver damage and its related neurobehavioral alterations in rats.

In this experimental study forty-eight Wistar rats were divided randomly into four groups (n = 12): C1 was the control group; C2 received a single-dose of TAA (350mg/kg; intraperitoneally) without any other treatment; E1 received TAA + 5 mg/kg CoQ10 (intraperitoneally); and E2 received TAA + 10 mg/kg CoQ10. After sacrificing the rats, liver enzymes and plasma-ammonia (NH4) were measured and histopathological analyses of the livers were carried out. Elevated-plus-maze, open-field, and forced-swimming tests were also performed to investigate behavioral correlations.

The serum levels of alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), and NH4 show significant increases (P < 0.05). The groups treated with CoQ10 were shown to have significantly lower clinical grade of encephalopathy (P = 0.001), higher locomotor activity (P = 0.000), and lower levels of depression (P = 0.000). Furthermore, it was also shown that CoQ10 treatment may lead to significant decreases in scores of centrilobular necrosis, apoptosis, inflammatory cell infiltration, vacuolization, and liver necrosis (P < 0.05).

Overall, CoQ10 was determined to have positive effects on liver injury and its related behavioral and biochemical changes.

• Acute liver Failure
• Behavioral Symptoms
• Coenzyme Q10
• Hyperammonemia
• Thioacetamide

Hepatic encephalopathy is a neuropsychiatric syndrome evolving from cerebral osmotic disturbances and oxidative/nitrosative stress. Ammonia, the main toxin of hepatic encephalopathy, triggers astrocyte senescence in an oxidative stress-dependent way. As miRNAs are critically involved in cell cycle regulation and their expression may be regulated by oxidative stress, we analysed, whether astrocyte senescence is a consequence of ammonia-induced miRNA expression changes. Using a combined miRNA and gene microarray approach, 43 miRNA species which were downregulated and 142 genes which were upregulated by NH₄Cl (5 mmol/l, 48 h) in cultured rat astrocytes were found. Ammonia-induced miRNA and gene expression changes were validated by qPCR and 43 potential miRNA target genes, including HO-1, were identified by matching upregulated mRNA species with predicted targets of miRNA species downregulated by ammonia. Inhibition of HO-1 targeting miRNAs which were downregulated by NH₄Cl strongly upregulated HO-1 mRNA and protein levels and inhibited astrocyte proliferation in a HO-1-dependent way. Preventing ammonia-induced upregulation of HO-1 by taurine (5 mmol/l) as well as blocking HO-1 activity by tin-protoporphyrine IX fully prevented ammonia-induced proliferation inhibition and senescence. The data suggest that ammonia induces astrocyte senescence through NADPH oxidase-dependent downregulation of HO-1 targeting miRNAs and concomitant upregulation of HO-1 at both mRNA and protein level.

• Mrp4
• ammonia
• astrocytes
• glutamine
• hepatic encephalopathy

• astrocyte
• heme oxygenase-1
• miRNA
• mitochondria
• neurodegeneration
• oxidative stress

• Acute Disease
• Ammonia/metabolism
• Animals
• Astrocytes/metabolism
• Astrocytes/ultrastructure
• Body Water/metabolism
• Brain Edema/etiology
• Brain Edema/physiopathology
• Cell Size
• Confounding Factors, Epidemiologic
• Homeostasis
• Humans
• Infections/complications
• Inflammation
• Intracranial Hypertension/etiology
• Intracranial Hypertension/physiopathology
• Ion Transport/physiology
• Liver Failure/chemically induced
• Liver Failure/complications
• Liver Failure/metabolism
• Mitogen-Activated Protein Kinases/metabolism
• NF-kappa B/metabolism
• Nerve Tissue Proteins/metabolism
• Nitrosation
• Oxidative Stress
• Research Design

• DK06331 NIDDK NIH HHS

Cerebral oedema is a devastating consequence of acute liver failure (ALF) and may be associated with the development of intracranial hypertension and death. In ALF, some patients may develop cerebral oedema and increased intracranial pressure but progression to life-threatening intracranial hypertension is less frequent than previously described, complicating less than one third of cases who have proceeded to coma since the advent of improved clinical care. The rapid onset of encephalopathy may be dramatic with the development of asterixis, delirium, seizures and coma. Cytotoxic and vasogenic oedema mechanisms have been implicated with a preponderance of experimental data favouring a cytotoxic mechanism. Astrocyte swelling is the most consistent neuropathological finding in humans with ALF and ammonia plays a definitive role in the development of cytotoxic brain oedema. The mechanism(s) by which ammonia induces astrocyte swelling remains unclear but glutamine accumulation within astrocytes has led to the osmolyte hypothesis. Current evidence also supports an alternate ‘Trojan horse’ hypothesis, with glutamine as a carrier of ammonia into mitochondria, where its accumulation results in oxidative stress, energy failure and ultimately astrocyte swelling. Although a complete breakdown of the blood-brain barrier is not evident in human ALF, increased permeation to water and other small molecules such as ammonia has been demonstrated resulting from subtle alterations in the protein composition of paracellular tight junctions. At present, there is no fully efficacious therapy for cerebral oedema other than liver transplantation and this reflects our incomplete knowledge of the precise mechanisms underlying this process which remain largely unknown.

• Cerebral oedema
• Acute liver failure
• Ammonia
• Hepatic encephalopathy
• Intracranial pressure
• Intracranial hypertension
• Cerebral blood flow

• Ammonia/metabolism
• Animals
• Astrocytes/metabolism
• Blood-Brain Barrier/metabolism
• Blood-Brain Barrier/physiopathology
• Brain/metabolism
• Brain/physiopathology
• Brain Edema/etiology
• Brain Edema/metabolism
• Brain Edema/physiopathology
• Brain Edema/therapy
• Capillary Permeability
• Disease Progression
• Energy Metabolism
• Glutamic Acid/metabolism
• Hepatic Encephalopathy/etiology
• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/physiopathology
• Hepatic Encephalopathy/therapy
• Humans
• Liver Failure, Acute/complications
• Liver Failure, Acute/metabolism
• Liver Failure, Acute/physiopathology
• Liver Failure, Acute/therapy
• Mitochondria/metabolism
• Mitochondrial Membrane Transport Proteins/metabolism
• Mitochondrial Permeability Transition Pore
• Oxidative Stress
• Prognosis
• Risk Factors

• Astrocytes
• NADPH oxidase
• Protein tyrosine nitration
• RNA oxidation
• Zinc

• Ammonia/metabolism
• Animals
• Astrocytes/cytology
• Astrocytes/metabolism
• Cells, Cultured
• Culture Media
• Gene Expression Profiling
• Glutamic Acid/metabolism
• Glutamine/metabolism
• Humans

• R01 DK063311 NIDDK NIH HHS
• DK063311 NIDDK NIH HHS

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.

Brain edema leading to high intracranial pressure is a lethal complication of acute liver failure (ALF), which is believed to be cytotoxic due to swelling of astrocytes. In addition to the traditional view that elevated levels of blood and brain ammonia are involved in the mechanism of brain edema in ALF, emerging evidence suggests that inflammatory cytokines also contribute to this process. We earlier reported that treatment of astrocyte cultures with a pathophysiological concentration of ammonia (5 mM NH₄Cl) resulted in the activation of nuclear factor-kappaB (NF-κB) and that inhibition of such activation diminished astrocyte swelling, suggesting a key role of NF-κB in the mechanism of ammonia-induced astrocyte swelling. Since cytokines are also well-known to activate NF-κB, this study examined for additive/synergistic effects of ammonia and cytokines in the activation of NF-κB and their role in astrocyte swelling.

Primary cultures of astrocytes were treated with ammonia and cytokines (TNF-α, IL-1, IL-6, IFN-γ, each at 10 ng/ml), individually or in combination, and cell volume was determined by the [³H]-O-methylglucose equilibration method. The effect of ammonia and cytokines on the activation of NF-κB was determined by immunoblots.

Cell swelling was increased by ammonia (43%) and by cytokines (37%) at 24 h. Simultaneous co-treatment with cytokines and ammonia showed no additional swelling. By contrast, cultures pretreated with ammonia for 24 h and then exposed to cytokines for an additional 24 h, showed a marked increase in astrocyte swelling (129%). Treatment of cultures with ammonia or cytokines alone also activated NF-κB (80-130%), while co-treatment had no additive effect. However, in cultures pre-treated with ammonia for 24 h, cytokines induced a marked activation of NF-κB (428%). BAY 11-7082, an inhibitor of NF-κB, completely blocked the astrocyte swelling in cultures pre-treated with ammonia and followed by the addition of a mixture of cytokines.

Our results indicate that ammonia and a mixture of cytokines each cause astrocyte swelling but when these agents are added simultaneously, no additive effects were found. On the other hand, when cells were initially treated with ammonia and 24 h later given a mixture of cytokines, a marked potentiation in cell swelling and NF-κB activation occurred. These data suggest that the potentiation in cell swelling is a consequence of the initial activation of NF-κB by ammonia. These findings provide a likely mechanism for the exacerbation of brain edema in patients with ALF in the setting of sepsis/inflammation.

• Aldehydes/analysis
• Aldehydes/blood
• Ammonia/analysis
• Ammonia/blood
• Ammonia/cerebrospinal fluid
• Animals
• Biomarkers/analysis
• Biomarkers/blood
• Biomarkers/cerebrospinal fluid
• Blotting, Western
• Brain/metabolism
• Brain/physiopathology
• Disease Models, Animal
• Frontal Lobe/metabolism
• Frontal Lobe/physiopathology
• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/physiopathology
• Hyperammonemia/complications
• Hyperammonemia/metabolism
• Hyperammonemia/physiopathology
• Liver Failure, Acute/complications
• Liver Failure, Acute/metabolism
• Liver Failure, Acute/physiopathology
• Male
• Oxidative Stress/physiology
• Portacaval Shunt, Surgical/adverse effects
• Protein Carbonylation/physiology
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species/metabolism

• Aging/metabolism
• Animals
• Blotting, Western
• Female
• Heme Oxygenase-1/metabolism
• Inflammation/drug therapy
• Interleukins/metabolism
• Lipid Peroxidation/drug effects
• Lipid Peroxides/metabolism
• Liver/drug effects
• Liver/enzymology
• Liver/metabolism
• Melatonin/pharmacology
• Nitric Oxide/metabolism
• Nitric Oxide Synthase Type II/metabolism
• Ovariectomy/adverse effects
• Oxidative Stress/drug effects
• Rats
• Rats, Wistar
• Tumor Necrosis Factor-alpha/metabolism

• Ammonia/toxicity
• Animals
• Astrocytes/drug effects
• Astrocytes/metabolism
• Astrocytes/pathology
• Brain Edema/chemically induced
• Cell Size
• Energy Metabolism
• Glutamine/metabolism
• Humans
• Liver Failure, Acute/chemically induced
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Mitogen-Activated Protein Kinases/physiology
• Oxidative Stress

• DK063311 NIDDK NIH HHS

• Ammonia/blood
• Animals
• Blood Urea Nitrogen
• Brain/metabolism
• Carnitine/therapeutic use
• Glutathione/blood
• Lipid Peroxidation/drug effects
• Liver/drug effects
• Liver/enzymology
• Liver Failure/chemically induced
• Liver Failure/metabolism
• Liver Failure/prevention & control
• Male
• Melatonin/therapeutic use
• Oxidative Stress/drug effects
• Protective Agents/therapeutic use
• Rats
• Rats, Wistar
• Thioacetamide
• Vitamin E/therapeutic use

• Animals
• Astrocytes/pathology
• Free Radicals/metabolism
• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/pathology
• Humans
• Osmosis
• Oxidative Stress
• Tyrosine/metabolism

• blood-brain barrier
• rats
• prehepatic portal hypertension

• Ammonia/blood
• Animals
• Blood Proteins/analysis
• Blood-Brain Barrier/physiopathology
• Capillary Permeability
• Cerebral Cortex/chemistry
• Cerebrospinal Fluid Proteins/analysis
• Coloring Agents
• Hemodynamics
• Hypertension, Portal/physiopathology
• Ligation
• Male
• Portal Pressure/physiology
• Portal Vein/physiopathology
• Rats
• Rats, Wistar
• Transferases/blood
• Water/analysis

• Brain Edema/etiology
• Brain Edema/therapy
• Hepatic Encephalopathy/etiology
• Hepatic Encephalopathy/therapy
• Humans
• Hypothermia, Induced/methods
• Intracranial Hypertension/etiology
• Intracranial Hypertension/therapy
• Liver Failure, Acute/complications
• Liver Failure, Acute/therapy

• Ammonia/toxicity
• Animals
• Aquaporins/physiology
• Astrocytes/drug effects
• Astrocytes/ultrastructure
• Cell Size
• Glutamine/physiology
• Glutathione/physiology
• Humans
• Lactic Acid/metabolism
• Mitochondria/drug effects
• Neurotransmitter Agents/physiology
• Oxidative Stress/physiology
• Permeability
• Receptors, GABA-A/physiology
• Steroids/physiology

• DK063311 NIDDK NIH HHS

• Cerebrovascular Circulation/physiology
• Disease Progression
• Female
• Hepatic Encephalopathy/diagnosis
• Hepatic Encephalopathy/physiopathology
• Humans
• Liver Failure, Acute/diagnosis
• Liver Failure, Acute/physiopathology
• Liver Function Tests
• Male
• Monitoring, Physiologic
• Predictive Value of Tests
• Risk Assessment
• Sensitivity and Specificity
• Severity of Illness Index

• Aging/metabolism
• Animals
• Cells, Cultured
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Lipid Peroxidation
• Melatonin/administration & dosage
• Melatonin/pharmacology
• Oxidative Stress
• Rats
• Rats, Wistar

• Ammonia/metabolism
• Animals
• Astrocytes/metabolism
• Brain/metabolism
• Brain/physiopathology
• Glutamine/metabolism
• Hepatic Encephalopathy/etiology
• Hepatic Encephalopathy/metabolism
• Hepatic Encephalopathy/physiopathology
• Humans
• Nerve Degeneration/metabolism
• Oxidative Stress/physiology
• Water-Electrolyte Balance/physiology

• DK063311 NIDDK NIH HHS

• Aging/physiology
• Animals
• Brain/cytology
• Brain/enzymology
• Brain/growth & development
• Cell Nucleus/enzymology
• Cells, Cultured
• Guanylate Cyclase
• Immunohistochemistry
• Male
• Neural Pathways/cytology
• Neural Pathways/growth & development
• Neurons/enzymology
• Neuropil/enzymology
• Nitric Oxide Synthase/biosynthesis
• Nitric Oxide Synthase Type II
• Nuclease Protection Assays
• RNA Probes
• RNA, Messenger/biosynthesis
• Rats
• Rats, Wistar
• Receptors, Cytoplasmic and Nuclear/biosynthesis
• Reverse Transcriptase Polymerase Chain Reaction
• Soluble Guanylyl Cyclase

• Animals
• Antioxidants/metabolism
• Biological Clocks/genetics
• Biological Clocks/physiology
• Circadian Rhythm/physiology
• Humans
• Isoenzymes/metabolism
• Kynuramine/chemistry
• Kynuramine/metabolism
• Melatonin/metabolism
• Mitochondria/metabolism
• Neoplasms/genetics
• Nuclear Proteins/genetics
• Nuclear Proteins/metabolism
• Oxidants/metabolism
• Oxidation-Reduction
• Oxidative Stress
• Period Circadian Proteins
• Quinone Reductases/metabolism
• Transcription Factors