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Sepehrinezhad A, Zarifkar A, Namvar G, Shahbazi A, Williams R. Astrocyte swelling in hepatic encephalopathy: molecular perspective of cytotoxic edema. Metab Brain Dis 2020; 35:559-578. [PMID: 32146658 DOI: 10.1007/s11011-020-00549-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 02/12/2020] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) may occur in patients with liver failure. The most critical pathophysiologic mechanism of HE is cerebral edema following systemic hyperammonemia. The dysfunctional liver cannot eliminate circulatory ammonia, so its plasma and brain levels rise sharply. Astrocytes, the only cells that are responsible for ammonia detoxification in the brain, are dynamic cells with unique phenotypic properties that enable them to respond to small changes in their environment. Any pathological changes in astrocytes may cause neurological disturbances such as HE. Astrocyte swelling is the leading cause of cerebral edema, which may cause brain herniation and death by increasing intracranial pressure. Various factors may have a role in astrocyte swelling. However, the exact molecular mechanism of astrocyte swelling is not fully understood. This article discusses the possible mechanisms of astrocyte swelling which related to hyperammonia, including the possible roles of molecules like glutamine, lactate, aquaporin-4 water channel, 18 KDa translocator protein, glial fibrillary acidic protein, alanine, glutathione, toll-like receptor 4, epidermal growth factor receptor, glutamate, and manganese, as well as inflammation, oxidative stress, mitochondrial permeability transition, ATP depletion, and astrocyte senescence. All these agents and factors may be targeted in therapeutic approaches to HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Asadollah Zarifkar
- Shiraz Neuroscience Research Center and Department of Physiology, Shiraz University of Medical Sciences (SUMS), Shiraz, Iran
| | - Gholamreza Namvar
- Department of Neuroscience and Cognition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Roger Williams
- The Institute of Hepatology London and Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK.
- Faculty of Life Sciences & Medicine, King's College London, London, UK.
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Huang Y, Su L, Wu J. Pyridoxine Supplementation Improves the Activity of Recombinant Glutamate Decarboxylase and the Enzymatic Production of Gama-Aminobutyric Acid. PLoS One 2016; 11:e0157466. [PMID: 27438707 PMCID: PMC4954698 DOI: 10.1371/journal.pone.0157466] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 05/30/2016] [Indexed: 11/19/2022] Open
Abstract
Glutamate decarboxylase (GAD) catalyzes the irreversible decarboxylation of L-glutamate to the valuable food supplement γ-aminobutyric acid (GABA). In this study, GAD from Escherichia coli K12, a pyridoxal phosphate (PLP)-dependent enzyme, was overexpressed in E. coli. The GAD produced in media supplemented with 0.05 mM soluble vitamin B6 analog pyridoxine hydrochloride (GAD-V) activity was 154.8 U mL-1, 1.8-fold higher than that of GAD obtained without supplementation (GAD-C). Purified GAD-V exhibited increased activity (193.4 U mg-1, 1.5-fold higher than that of GAD-C), superior thermostability (2.8-fold greater than that of GAD-C), and higher kcat/Km (1.6-fold higher than that of GAD-C). Under optimal conditions in reactions mixtures lacking added PLP, crude GAD-V converted 500 g L-1 monosodium glutamate (MSG) to GABA with a yield of 100%, and 750 g L-1 MSG with a yield of 88.7%. These results establish the utility of pyridoxine supplementation and lay the foundation for large-scale enzymatic production of GABA.
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Affiliation(s)
- Yan Huang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Biotechnology and Key Laboratory of Industrial Biotechnology Ministry of Education, Jiangnan University, Wuxi, China
| | - Lingqia Su
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Biotechnology and Key Laboratory of Industrial Biotechnology Ministry of Education, Jiangnan University, Wuxi, China
| | - Jing Wu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Biotechnology and Key Laboratory of Industrial Biotechnology Ministry of Education, Jiangnan University, Wuxi, China
- * E-mail:
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Butterworth RF. Neurosteroids in hepatic encephalopathy: Novel insights and new therapeutic opportunities. J Steroid Biochem Mol Biol 2016; 160:94-7. [PMID: 26589093 DOI: 10.1016/j.jsbmb.2015.11.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 10/22/2015] [Accepted: 11/09/2015] [Indexed: 12/13/2022]
Abstract
Hepatic encephalopathy (HE) is a serious neuropsychiatric disorder resulting from liver failure. Symptoms of HE include mild cognitive impairment, stupor and coma. Morphological changes to neuroglia (both astrocytes and microglia) occur in HE consisting of cytotoxic brain edema (astrocyte swelling) in acute liver failure and Alzheimer type-2 astrocytosis in cirrhosis. Visual-evoked responses in animals with liver failure and HE manifest striking similarities to those in animals treated with agonists of the GABA-A receptor complex. Neurosteroids are synthesized in brain following activation of translocator protein (TSPO), a mitochondrial neuroglial cholesterol-transporter protein. TSPO sites are activated in both animal models of HE as well as in autopsied brain tissue from HE patients. Activation of TSPO sites results in increased cholesterol transport into the mitochondrion followed by stimulation of a metabolic pathway culminating in the synthesis of allopregnanolone (ALLO) and tetrahydrodeoxycorticosterone (THDOC), neurosteroids with potent positive allosteric modulatory action on the GABA-A receptor complex. Concentrations of ALLO and THDOC in brain tissue from mice with HE resulting from toxic liver injury are sufficient to induce sedation in animals of the same species and significant increases in concentrations of ALLO have been reported in autopsied brain tissue from cirrhotic patients with HE leading to the proposal that "increased GABAergic tone" in HE results from that increased brain concentrations of this neurosteroid. Agents with the potential to decrease neurosteroid synthesis and/or prevent their modulatory actions on the GABA-A receptor complex may provide novel approaches to the management and treatment of HE. Such agents include indomethacin, benzodiazepine receptor inverse agonists and a novel series of compounds known as GABA-A receptor-modulating steroid antagonists (GAMSA).
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Lidbury JA, Cook AK, Steiner JM. Hepatic encephalopathy in dogs and cats. J Vet Emerg Crit Care (San Antonio) 2016; 26:471-87. [PMID: 27060899 DOI: 10.1111/vec.12473] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 11/04/2014] [Accepted: 11/07/2014] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To comparatively review the pathogenesis, clinical presentation, diagnosis, and management of hepatic encephalopathy (HE) in dogs and cats. DATA SOURCES The Medline database was searched for articles related to HE in people, dogs, and cats. Articles published within the last 5 years were given special importance. HUMAN DATA SYNTHESIS The pathogenesis of HE is complex and incompletely understood, but ammonia appears to play a central role. Hyperammonemia leads to accumulation of glutamine in astrocytes, with subsequent astrocyte swelling and neurological dysfunction. The development of HE in patients with hepatic cirrhosis is a poor prognostic indicator. The fermentable disaccharide lactulose and the antimicrobial rifaximin are US Food and Drug Administration approved treatments for human HE. Severe protein restriction is no longer recommended for patients with this condition. VETERINARY DATA SYNTHESIS HE is often associated with portosystemic shunting in dogs and cats. Ammonia plays a central role in the pathogenesis of HE in dogs and cats, but other factors such as manganese and endogenous benzodiazepines may also contribute. Recently, a soy protein-based diet was found to be beneficial in treating canine HE. Severe dietary protein restriction is likely to be detrimental in affected animals. There have been no clinical trials of drugs routinely used in the management HE in veterinary medicine, but lactulose and antimicrobials such as metronidazole are well-established treatments. CONCLUSIONS HE is a potentially life-threatening condition that is probably underdiagnosed in companion animals. Although various treatment recommendations have been proposed, there is a lack of evidence in the veterinary literature regarding optimal strategies for the management of this condition. As our understanding of the pathogenesis of HE in dogs and cats evolves, novel diagnostic tests and therapeutic agents may become available.
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Affiliation(s)
- Jonathan A Lidbury
- Department of Veterinary Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843
| | - Audrey K Cook
- Department of Veterinary Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843
| | - Jörg M Steiner
- Department of Veterinary Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843
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Mladenović D, Hrnčić D, Rašić-Marković A, Macut D, Stanojlović O. The Influence of Finasteride on Mean and Relative Spectral Density of EEG Bands in Rat Model of Thioacetamide-Induced Hepatic Encephalopathy. Neurotox Res 2016; 30:150-8. [PMID: 26951455 DOI: 10.1007/s12640-016-9610-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 02/12/2016] [Accepted: 02/15/2016] [Indexed: 12/23/2022]
Abstract
Liver failure is associated with a neuropsychiatric syndrome, known as hepatic encephalopathy (HE). Finasteride, inhibitor of neurosteroid synthesis, may improve the course of HE. The aim of our study was to investigate the influence of finasteride on mean and relative power density of EEG bands, determined by spectral analysis, in rat model of thioacetamide-induced HE. Male Wistar rats were divided into groups: (1) control; (2) thioacetamide-treated group, TAA (900 mg/kg); (3) finasteride-treated group, FIN (150 mg/kg); and (4) group treated with finasteride (150 mg/kg) and thioacetamide (900 mg/kg), FIN + TAA. Daily doses of FIN (50 mg/kg) and TAA (300 mg/kg) were administered during 3 subsequent days, and in FIN + TAA group FIN was administered 2 h before every dose of TAA. EEG was recorded 22-24 h after treatment and analyzed by fast Fourier transformation. While TAA did not induce significant changes in the beta band, mean and relative power in this band were significantly higher in FIN + TAA versus control group (p < 0.01). TAA caused a significant decline in mean power in alpha, theta, and delta band, and in FIN + TAA group the mean power in these bands was significantly higher compared with control. While in TAA group relative power was significantly decreased in theta (p < 0.01) and increased in delta band (p < 0.01) versus control, the opposite changes were found in FIN + TAA group: an increase in theta (p < 0.01) and a decrease in delta relative power (p < 0.01). In this study, finasteride pretreatment caused EEG changes that correspond to mild TAA-induced HE.
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Affiliation(s)
- D Mladenović
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Dr Subotica 9, Belgrade, Serbia
| | - D Hrnčić
- Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Višegradska 26/II, 11000, Belgrade, Serbia
| | - A Rašić-Marković
- Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Višegradska 26/II, 11000, Belgrade, Serbia
| | - Dj Macut
- Clinic for Endocrinology, Diabetes and Diseases of Metabolism, Faculty of Medicine, University of Belgrade, Dr Subotića 13, Belgrade, Serbia
| | - O Stanojlović
- Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Višegradska 26/II, 11000, Belgrade, Serbia.
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Wang XY, Xie RX, Zhang JG, Zhang DK. Role of neurosteroids in hepatic encephalopathy. Shijie Huaren Xiaohua Zazhi 2014; 22:5086-5091. [DOI: 10.11569/wcjd.v22.i33.5086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric manifestation of chronic or acute liver disease. Neurosteroids are synthesized from cholesterol and its precursors by glial cells, oligodendrocytes and neurons in the brain. The mechanisms by which neurosteroids affect brain function may involve both genetic and non-genetic effects. On one hand, neurosteroids bind and modulate different types of neuronal membrane receptors, including gamma-amino butyric acid-A receptor (GABA-A), N-methyl-D-aspartic acid receptor (NMDA), 5-hydroxytryptamine 3 (5-HT3) and opioid receptors which have been showed to be involved in HE. On the other hand, some neurosteroids bind to intracellular receptors through which they also regulate gene expression. Of note, neurosteroids play a role in the pathogenesis of HE through inhibiting long-term potentiation. Neurosteroids might provide a new avenue for HE treatment.
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Palomero-Gallagher N, Zilles K. Neurotransmitter receptor alterations in hepatic encephalopathy: a review. Arch Biochem Biophys 2013; 536:109-21. [PMID: 23466244 DOI: 10.1016/j.abb.2013.02.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 02/18/2013] [Accepted: 02/19/2013] [Indexed: 01/07/2023]
Abstract
Hepatic encephalopathy (HE), a complex neuropsychiatric syndrome with symptoms ranging from subtle neuropsychiatric and motor disturbances to deep coma and death, is thought to be a clinical manifestation of a low-grade cerebral oedema associated with an altered neuron-astrocyte crosstalk and exacerbated by hyperammonemia and oxidative stress. These events are tightly coupled with alterations in neurotransmission, either in a causal or a causative manner, resulting in a net increase of inhibitory neurotransmission. Therefore, research focussed mainly on the potential role of γ-aminobutyric acid-(GABA) or glutamate-mediated neurotransmission in the pathophysiology of HE, though roles for other neurotransmitters (e.g. serotonin, dopamine, adenosine and histamine) or for neurosteroids or endogenous benzodiazepines have also been suggested. Therefore, we here review HE-related alterations in neurotransmission, focussing on changes in the levels of classical neurotransmitters and the neuromodulator adenosine, variations in the activity and/or concentrations of key enzymes involved in their metabolism, as well as in the densities of their receptors.
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Mladenović D, Radosavljević T, Hrnčić D, Rašić-Marković A, Puškaš N, Maksić N, Djuric D, Stanojlović O. Behavioral and electroencephalographic manifestations of thioacetamide-induced encephalopathy in rats. Can J Physiol Pharmacol 2012; 90:1219-27. [PMID: 22913436 DOI: 10.1139/y2012-088] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The aim of our study was to investigate the behavioral and electroencephalographic manifestations of thioacetamide-induced encephalopathy in rats. Male Wistar rats were divided among (i) control, saline-treated, and (ii) thioacetamide-treated groups (TAA(300) (300 mg/kg body mass); TAA(600) (600 mg/kg); and TAA(900) (900 mg/kg)). The daily dose of thioacetamide (300 mg/kg) was administered intraperitoneally once (TAA(300)), twice (TAA(600)), or 3 times (TAA(900)), on subsequent days. Behavioral manifestations were determined at 0, 2, 4, 6, and 24 h, while electroencephalographic changes were recorded 22-24 h after the last dose. General motor activity and exploratory behavior, as well as head shake, auditory startle reflex, placement, and equlibrium tests were diminished in the TAA(600) and TAA(900) groups compared with the control, and were absent in the TAA(900) group 24 h after treatment. Corneal, withdrawal, grasping, and righting reflexes were significantly diminished in the TAA(900) group compared with the control. Mean electroencephalographic power spectra density was significantly higher in TAA(300) and TAA(600) and lower in the TAA(900) group by comparison with the control. Only a score of 3 (mean dominant frequency ≤ 7.3 Hz and δ relative power ≥ 45%) was observed in the TAA(900) group. Thioacetamide induces encephalopathy in rats in a dose-dependent manner. A dose of 900 mg/kg TAA may be used as a suitable model of all stages of hepatic encephalopathy.
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Affiliation(s)
- Dušan Mladenović
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Serbia
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Patel D, McPhail MJW, Cobbold JFL, Taylor-Robinson SD. Hepatic encephalopathy. Br J Hosp Med (Lond) 2012; 73:79-85. [DOI: 10.12968/hmed.2012.73.2.79] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
| | | | | | - SD Taylor-Robinson
- the Department of Medicine, Hepatology and Gastroenterology Section, Imperial College London, St Mary's Hospital Campus, London W2 1NY
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10
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Abstract
Hepatic encephalopathy is characterized by neuropsychiatric abnormalities in patients with liver failure. Severe hepatic encephalopathy is an indication for liver transplantation as it portends poor outcome. Treatment of hepatic encephalopathy involves correction of precipitating factors such as sepsis, gastrointestinal bleeding, medications, and electrolyte imbalance. Effective therapies include lactulose and antibiotics such as neomycin, metronidazole, and rifaximin.
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Affiliation(s)
- Vinay Sundaram
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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Ahboucha S, Jiang W, Chatauret N, Mamer O, Baker GB, Butterworth RF. Indomethacin improves locomotor deficit and reduces brain concentrations of neuroinhibitory steroids in rats following portacaval anastomosis. Neurogastroenterol Motil 2008; 20:949-57. [PMID: 18482252 DOI: 10.1111/j.1365-2982.2008.01132.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric complication of both acute and chronic liver failure characterized by progressive neuronal inhibition. Some neurosteroids are potent positive allosteric modulators of the gamma-aminobutyric acid (GABA)-A receptor complex, and 'increased GABAergic tone' has been proposed to explain the neuroinhibition characteristics of HE. Brain levels of the neurosteroids pregnenolone, allopregnanolone and tetrahydrodesoxycorticosterone (THDOC) and the functional status of the GABA-A receptor complex were assessed in rats following portacaval anastomosis (PCA). Effects of indomethacin, an inhibitor of the 3alpha-hydroxysteroid dehydrogenase enzyme involved in neurosteroid synthesis, on PCA rat locomotor activity and brain neurosteroid levels were also assessed. Significant increases of the neurosteroid pregnenolone (2.6-fold), allopregnanolone (1.7-fold) and THDOC (4.7-fold) were observed in brains of PCA rats. Brain levels of these neurosteroids were in the nanomolar range, sufficient to exert positive allosteric modulatory effects at the GABA-A receptor. Indomethacin (0.1-5 mg kg(-1)) ameliorated dose-dependently the locomotor deficit of PCA rats and concomitantly normalized brain levels of allopregnanolone and THDOC. Increased brain levels of neurosteroids with positive allosteric modulatory actions at the neuronal GABA-A receptor offer a cogent explanation for the notion of 'increased GABAergic tone' in HE. Pharmacological approaches using agents that either reduce neurosteroid synthesis or modulate the neurosteroid site on GABA-A receptor could offer new therapeutic tools for the management and treatment of HE.
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Affiliation(s)
- S Ahboucha
- Neuroscience Research Unit, Université de Montréal, CHUM (Hôpital Saint-Luc), Montreal, QC, Canada.
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Vaquero J, Butterworth RF. Mechanisms of brain edema in acute liver failure and impact of novel therapeutic interventions. Neurol Res 2008; 29:683-90. [PMID: 18173908 DOI: 10.1179/016164107x240099] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Continued elucidation of the mechanisms of brain edema in acute liver failure (ALF) has established ammonia and the astrocyte as major players in its pathogenesis. The metabolism of ammonia to glutamine appears to be a requisite, and is followed by an osmotic disturbance in the brain, mitochondrial dysfunction with oxidative/nitrosative stress, and alterations of brain glucose metabolism. Cerebral blood flow (CBF) is also altered in ALF and strongly influence the development of brain edema and intracranial hypertension. Additional factors such as systemic inflammation, alterations of the brain extracellular concentration of amino acids and neurotransmitters, and others have been identified and may contribute to the cerebral alterations of ALF. Such pathophysiologic insights are reflected in the various clinical trials of novel therapeutic interventions using ammonia-lowering agents, N-acetylcysteine, hypertonic saline, indomethacin, high-volume plasmapheresis, bio-artificial liver assist devices, albumin dialysis and mild hypothermia.
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Affiliation(s)
- Javier Vaquero
- Neuroscience Research Unit, Hôpital Saint-Luc (CHUM), Université de Montréal, Montréal, H2X3J4, QC., Canada
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Ahboucha S, Butterworth RF. The neurosteroid system: an emerging therapeutic target for hepatic encephalopathy. Metab Brain Dis 2007; 22:291-308. [PMID: 17823858 DOI: 10.1007/s11011-007-9065-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Both acute and chronic liver failure induce cerebral complications known as hepatic encephalopathy (HE) and thought to selectively involve brain astrocytes. Alterations of astrocytic-neuronal cross talk occurs affecting brain function. In acute liver failure, astrocyte undergo swelling, which results in increased intracranial pressure and may lead to brain herniation. In chronic liver failure, Alzheimer-type II astrocytosis is a characteristic change. Neurosteroids (NS) synthesized in the brain mainly by astrocytes independent of peripheral steroidal sources (adrenals and gonads) are suggested to play a role in HE. NS bind and modulate different types of membrane receptors. Effects on the gamma amino butyric acid (GABA)-A receptor complex are the most extensively studied. For example, the NS tetrahydroprogesterone (allopregnanolone), and tetrahydrodeoxycorticosterone (THDOC) are potent positive allosteric modulators of GABA-A receptors. As a consequence of modulation of these receptors, NS are well-known to modulate inhibitory neurotransmission in the central nervous system. Some NS bind to intracellular receptors, and in this way may also regulate gene expression. In HE, it has been well documented that neurotransmission and gene expression alterations occur during the progression of the disease. This review summarizes findings of relevance for the involvement of NS in human and experimental HE.
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Affiliation(s)
- Samir Ahboucha
- Neuroscience Research Unit, CHUM-Campus Saint-Luc, 1058 St-Denis, Montreal, Quebec, Canada.
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Ahboucha S, Butterworth RF. The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy. Neurochem Int 2007; 52:575-87. [PMID: 17610999 DOI: 10.1016/j.neuint.2007.05.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2007] [Revised: 04/23/2007] [Accepted: 05/03/2007] [Indexed: 01/09/2023]
Abstract
Hepatic encephalopathy (HE) is a serious cerebral complication of both acute and chronic liver failure. In acute liver failure, astrocytes undergo swelling which results in increased intracranial pressure and may lead to brain herniation and death. In chronic liver failure, Alzheimer-type II astrocytosis is the characteristic neuropathologic finding. Patients with liver failure manifest severe alterations of their quality of life including sleep disorders as well as memory, learning, and locomotor abnormalities. Neurosteroids (NS) are synthesized in the brain mainly by astrocytes independent of peripheral steroidal sources (adrenals and gonads) and are suggested to play a role in the pathogenesis of HE. NS bind and modulate different types of neural receptors; effects on the gamma amino butyric acid (GABA)-A receptor complex are the most extensively studied. For example, the NS tetrahydroprogesterone (allopregnanolone), and tetrahydrodeoxycorticosterone (THDOC) are potent positive allosteric modulators of the GABA-A receptor. As a consequence of modulation of these receptors, NS stimulate inhibitory neurotransmission in the CNS, and neuroinhibitory changes including "increased GABA-ergic tone" have been suggested as pathophysiological mechanisms in HE. Moreover, some NS bind to intracellular receptors through which they also regulate gene expression, and there is substantial evidence confirming that expression of genes coding for key astrocytic and neuronal proteins are altered in HE. This review summarizes findings consistent with the involvement of NS in human and experimental HE.
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Affiliation(s)
- Samir Ahboucha
- Neuroscience Research Unit, Hôpital Saint-Luc (CHUM), 1058 St-Denis, Montreal, Quebec, Canada H2X 3J4
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Cagnin A, Taylor-Robinson SD, Forton DM, Banati RB. In vivo imaging of cerebral "peripheral benzodiazepine binding sites" in patients with hepatic encephalopathy. Gut 2006; 55:547-53. [PMID: 16210399 PMCID: PMC1856189 DOI: 10.1136/gut.2005.075051] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS One proposed mechanism whereby hepatic encephalopathy (HE) leads to loss of brain function is dysregulated synthesis of neurosteroids. Mitochondrial synthesis of neurosteroids is regulated by "peripheral benzodiazepine binding sites" (PBBS). Expressed in the brain by activated glial cells, PBBS can be measured in vivo by the specific ligand [11C](R)-PK11195 and positron emission tomography (PET). Recently, it has been suggested that PBBS expressing glial cells may play a role in the general inflammatory responses seen in HE. Therefore, we measured PBBS in vivo in the brains of patients with minimal HE using [11C](R)-PK11195 PET. METHODS Five patients with minimal HE and biopsy proven cirrhosis of differing aetiology were assessed with a neuropsychometric battery. Regional expression of PBBS in the brain was detected by [11C](R)-PK11195 PET. RESULTS All patients showed brain regions with increased [11C](R)-PK11195 binding. Significant increases in glial [11C](R)-PK11195 binding were found bilaterally in the pallidum, right putamen, and right dorsolateral prefrontal region. The patient with the most severe cognitive impairment had the highest increases in regional [11C](R)-PK11195 binding. CONCLUSION HE is associated with increased cerebral binding of [11C](R)-PK11195 in vivo, reflecting increased expression of PBBS by glial cells. This supports earlier experimental evidence in rodent models of liver failure, suggesting that an altered glial cell state, as evidenced by the increase in cerebral PBBS, might be causally related to impaired brain functioning in HE.
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Affiliation(s)
- A Cagnin
- Department of Neurosciences, University of Padova, Padova, Italy
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Ahboucha S, Pomier-Layrargues G, Mamer O, Butterworth RF. Increased levels of pregnenolone and its neuroactive metabolite allopregnanolone in autopsied brain tissue from cirrhotic patients who died in hepatic coma. Neurochem Int 2006; 49:372-8. [PMID: 16563564 DOI: 10.1016/j.neuint.2006.02.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2005] [Revised: 02/06/2006] [Accepted: 02/09/2006] [Indexed: 11/15/2022]
Abstract
It has been suggested that neurosteroids with agonist properties at the central GABA-A receptor are implicated in the pathogenesis of hepatic encephalopathy (HE) in chronic liver disease. In order to address this issue, gas chromatography/mass spectrometry was used to measure the neurosteroids pregnenolone, allopregnanolone, and tetrahydrodeoxycorticosterone (THDOC) in postmortem brain tissue from controls, cirrhotic patients who died without HE, a patient who died in uremic coma, and cirrhotic patients who died in hepatic coma. Exposure of rat cerebral cortical membranes to brain extracts from hepatic coma patients resulted in a 53% (p < 0.001) increase in binding of [3H]muscimol, a GABA-A receptor ligand. Subsequent GC/MS analysis showed that concentrations of the GABA-A receptor agonist neurosteroid allopregnanolone were significantly increased in brain tissue from hepatic coma patients compared to patients without HE or controls (p < 0.001). Brain allopregnanolone concentrations were significantly correlated with the magnitude of induction of [3H]muscimol binding (r2 = 0.82, p < 0.0001). Concentrations of allopregnanolone comparable to those observed in hepatic coma brains are pathophysiologically relevant. Concentrations of the neurosteroid precursor pregnenolone were also increased in brain tissue from hepatic coma patients, while those of a second neurosteroid THDOC were below the levels of detection in all groups. Brain concentrations of benzodiazepine receptor ligands estimated by radioreceptor assay were not significantly increased in cirrhotic patients with or without hepatic coma. These findings suggest that increased levels of allopregnanolone rather than "endogenous benzodiazepines" offer a cogent explanation for the phenomenon of "increased GABAergic tone" previously proposed in HE.
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Affiliation(s)
- Samir Ahboucha
- Neuroscience Research Unit, CHUM (Hôpital Saint-Luc) Quebec, Canada H2X 3J4
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Ahboucha S, Butterworth RF. Role of endogenous benzodiazepine ligands and their GABA-A--associated receptors in hepatic encephalopathy. Metab Brain Dis 2005; 20:425-37. [PMID: 16382352 DOI: 10.1007/s11011-005-7928-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Benzodiazepine receptor ligands are suggested to play a role in the pathogenesis of hepatic encephalopathy (HE). Accumulation of these ligands in brain was suggested to explain in part the notion of"increased GABAergic tone," the rational for which arose initially from reports of a beneficial effect of the selective benzodiazepine antagonist flumazenil in HE patients. It was suggested on the basis of the effect of flumazenil in human HE that liver failure may result in alterations of the density and/or affinity of the benzodiazepine-associated GABA-A receptor site. Subsequent controlled-clinical trials showed that fumazenil had a transient beneficial effect in only a subpopulation of HE patients. In contrast to the antagonists, partial inverse agonists of the benzodiazepine receptor have unequivocal beneficial effects on behavioral and electro-physiological performance in all experimental models of HE studied so far. Benzodiazepine-associated GABA-A receptors have consistently been demonstrated to be unaltered in both human and experimental HE. Contrary to initial reports, the so-called "endogenous benzodiazepines" do not appear to be significantly related to the pathogenesis of HE. On the other hand, nonbenzodiazepine GABA-A receptor complex modulators, such as neuro-steroids, recently identified in brain in human and experimental HE, may provide a new mechanistic basis for this disorder and lead to novel treatments for human HE.
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Affiliation(s)
- Samir Ahboucha
- Neuroscience Research Unit, CHUM-Hôpital Saint-Luc, Montreal, Quebec, Canada
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Ahboucha S, Layrargues GP, Mamer O, Butterworth RF. Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann Neurol 2005; 58:169-70. [PMID: 15984019 DOI: 10.1002/ana.20534] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Li XQ, Dong L, Liu ZH, Luo JY. Expression of gamma-aminobutyric acid A receptor subunits α 1, β 1, γ 2 mRNA in rats with hepatic encephalopathy. World J Gastroenterol 2005; 11:3319-22. [PMID: 15929193 PMCID: PMC4316074 DOI: 10.3748/wjg.v11.i21.3319] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mRNA expression of gamma-aminobutyric acid A (GABAA) receptor subunits α1, β1, γ2 in different parts of the brain of rats with hepatic encephalopathy.
METHODS: Twelve adult male Sprague-Dawley rats were randomly divided into two groups: (1) hepatic encephalopathy model group (n = 6), which was induced by intraperitoneal injection of thioacetamide (TAA, 350 mg/kg) for three consecutive days; (2) control group (n = 6), in which the rats were treated with same dose of normal saline solution. After the freeze slice of cerebrum was made, in situ hybridization was used to detect the mRNA of GABAA receptor subunits α1, β1, and γ2 in rat cerebral cortex, basal nuclei, substantia nigra and hippocampi. Image data were collected and analyzed quantitatively by QWin550CW model image signal gather and analysis system.
RESULTS: In rats with hepatic encephalopathy, mRNA expression levels of GABAA receptor subunits α1, β1 increased significantly in basal nuclei, substantia nigra pars compacta, substantia nigra pars reticularis and hippocampi (144.7±15.67/184.14±4.41, 60.61±33.66/113.07±32.44, 87.71± 21.25/128.40±18.85, 122.34±5.56/161.60±4.56, 123.29±5.21/140.65±4.15, 123.40±4.42/140.09±4.52, 124.76±4.18/140.09±4.12, 141.62±15.09/182.80 ±5.20, 69.13±30.74/134.21±43.76, 87.87±25.16/151.01±19.49, 122.14±6.30 /162.33±3.92, 122.81±5.09/137.19±7.12, 123.00±4.63/138.11±5.92, 125.75 ±2.43/138.81±6.10, P<0.01), but did not change in the cerebral cortex compared to the control group. Similar changes were found in the mRNA expression levels of GABAA receptor subunit γ2, which increased significantly in basal nuclei, substantia nigra pars compacta, substantia nigra pars reticularis (136.81±26.41/167.97±16.23, 51.00±36.14/113.18±36.52, 86.35±20.30/ 126.90±19.74, P<0.01), CA1 of hippocampal (162.15±9.05/178.62±6.45, P<0.05), and no changes were found in the cerebral cortex and CA2, CA3, CA4 of hippocampi.
CONCLUSION: In rats with hepatic encephalopathy, mRNA expression levels of GABAA receptor subunits α1, β1, γ2 increase significantly in basal nuclei, substantia nigra and hippocampi, suggesting that the changes of mRNA expression levels in GABAA receptor subunits may contribute to the pathogenesis of hepatic encephalopathy.
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Affiliation(s)
- Xiao-Qing Li
- Department of Gastroenterology, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Ahboucha S, Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at GABA from the molecular standpoint. Metab Brain Dis 2004; 19:331-43. [PMID: 15554425 DOI: 10.1023/b:mebr.0000043979.58915.41] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with either acute or chronic liver failure. More than two decades ago, the role of altered GABAergic neurotransmission was proposed following evidence of "increased GABAergic tone" in HE. Increased GABAergic tone was based on several observations: (i) Similarity of visual evoked response potential patterns between rabbits with galactosamine-induced fulminant hepatic failure and animals treated with various allosteric agonists of the GABA receptor complex (GRC). (ii) Spontaneous activities of isolated Purkinje neurons from rabbits with galactosamine-induced fulminant hepatic failure are more depressed by GRC modulator compounds compared to normal animals. (iii) Flumazenil, a high selective benzodiazepine antagonist at the GRC, ameliorates behavioral symptoms and EEG activity in some HE patients. Pathophysiological mechanisms put forward to explain increased GABAergic tone in HE include (1) increase in brain GABA content due to increased brain GABA uptake through altered permeability of the blood brain barrier, (2) alteration of the integrity of constituents of the GRC, and (3) increase of endogenous GRC modulators such as benzodiazepines (and more recently neurosteroids) with potent agonist properties at the GRC. Studies performed subsequently excluded alterations of either GABA content or GRC integrity in favor of increased brain concentrations of endogenous agonists. While the role of endogenous benzodiazepines remains controversial, the presence of neurosteroids with GABA agonist properties affords a plausible explanation for increased GABAergic tone in HE.
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Affiliation(s)
- Samir Ahboucha
- Neuroscience Research Unit, CHUM (Hopital Saint-Luc), Montreal, Quebec, Canada
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