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Poplawski J, Montina T, Metz GAS. Early life stress shifts critical periods and causes precocious visual cortex development. PLoS One 2024; 19:e0316384. [PMID: 39739746 DOI: 10.1371/journal.pone.0316384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 12/10/2024] [Indexed: 01/02/2025] Open
Abstract
The developing nervous system displays remarkable plasticity in response to sensory stimulation during critical periods of development. Critical periods may also increase the brain's vulnerability to adverse experiences. Here we show that early-life stress (ELS) in mice shifts the timing of critical periods in the visual cortex. ELS induced by animal transportation on postnatal day 12 accelerated the opening and closing of the visual cortex critical period along with earlier maturation of visual acuity. Staining of a molecular correlate that marks the end of critical period plasticity revealed premature emergence of inhibitory perineuronal nets (PNNs) following ELS. ELS also drove lasting changes in visual cortex mRNA expression affecting genes linked to psychiatric disease risk, with hemispheric asymmetries favoring the right side. NMR spectroscopy and a metabolomics approach revealed that ELS was accompanied by activated energy metabolism and protein biosynthesis. Thus, ELS may accelerate visual system development, resulting in premature opening and closing of critical period plasticity. Overall, the data suggest that ELS desynchronizes the orchestrated temporal sequence of regional brain development potentially leading to long-term functional deficiencies. These observations provide new insights into a neurodevelopmental expense to adaptative brain plasticity. These findings also suggest that shipment of laboratory animals during vulnerable developmental ages may result in long lasting phenotypes, introducing critical confounds to the experimental design.
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Affiliation(s)
- Janet Poplawski
- Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada
- Institute for Genetics and Cancer, University of Edinburgh, Edinburgh, Midlothian, United Kingdom
| | - Tony Montina
- Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, AB, Canada
| | - Gerlinde A S Metz
- Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada
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Prasad SK, Acharjee A, Singh VV, Trigun SK, Acharjee P. Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction. Metab Brain Dis 2024; 39:1649-1665. [PMID: 39120853 DOI: 10.1007/s11011-024-01407-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
Cerebral function is linked to a high level of metabolic activity and relies on glucose as its primary energy source. Glucose aids in the maintenance of physiological brain activities; as a result, a disruption in metabolism has a significant impact on brain function, launching a chain of events that leads to neuronal death. This metabolic insufficiency has been observed in a variety of brain diseases and neuroexcitotoxicity disorders, including hepatic encephalopathy. It is a significant neurological complication that develops in people with liver disease, ranging from asymptomatic abnormalities to coma. Hyperammonemia is the main neurotoxic villain in the development of hepatic encephalopathy and induces a wide range of complications in the brain. The neurotoxic effects of ammonia on brain function are thought to be mediated by impaired glucose metabolism. Accordingly, in this review, we provide an understanding of deranged brain energy metabolism, emphasizing the role of glucose metabolic dysfunction in the pathogenesis of hepatic encephalopathy. We also highlighted the differential metabolic profiles of brain cells and the status of metabolic cooperation between them. The major metabolic pathways that have been explored are glycolysis, glycogen metabolism, lactate metabolism, the pentose phosphate pathway, and the Krebs cycle. Furthermore, the lack of efficacy in current hepatic encephalopathy treatment methods highlights the need to investigate potential therapeutic targets for hepatic encephalopathy, with regulating deficient bioenergetics being a viable alternative in this case. This review also demonstrates the importance of the development of glucose metabolism-focused disease diagnostics and treatments, which are now being pursued for many ailments.
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Affiliation(s)
- Shambhu Kumar Prasad
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Arup Acharjee
- Department of Zoology, University of Allahabad, Prayagraj, 211002, India.
| | - Vishal Vikram Singh
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Surendra Kumar Trigun
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Papia Acharjee
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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Jiang P, Zhang Z, Yu Q, Wang Z, Diao L, Li D. ToxDAR: A Workflow Software for Analyzing Toxicologically Relevant Proteomic and Transcriptomic Data, from Data Preparation to Toxicological Mechanism Elucidation. Int J Mol Sci 2024; 25:9544. [PMID: 39273492 PMCID: PMC11394870 DOI: 10.3390/ijms25179544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/26/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Exploration of toxicological mechanisms is imperative for the assessment of potential adverse reactions to chemicals and pharmaceutical agents, the engineering of safer compounds, and the preservation of public health. It forms the foundation of drug development and disease treatment. High-throughput proteomics and transcriptomics can accurately capture the body's response to toxins and have become key tools for revealing complex toxicological mechanisms. Recently, a vast amount of omics data related to toxicological mechanisms have been accumulated. However, analyzing and utilizing these data remains a major challenge for researchers, especially as there is a lack of a knowledge-based analysis system to identify relevant biological pathways associated with toxicity from the data and to establish connections between omics data and existing toxicological knowledge. To address this, we have developed ToxDAR, a workflow-oriented R package for preprocessing and analyzing toxicological multi-omics data. ToxDAR integrates packages like NormExpression, DESeq2, and igraph, and utilizes R functions such as prcomp and phyper. It supports data preparation, quality control, differential expression analysis, functional analysis, and network analysis. ToxDAR's architecture also includes a knowledge graph with five major categories of mechanism-related biological entities and details fifteen types of interactions among them, providing comprehensive knowledge annotation for omics data analysis results. As a case study, we used ToxDAR to analyze a transcriptomic dataset on the toxicology of triphenyl phosphate (TPP). The results indicate that TPP may impair thyroid function by activating thyroid hormone receptor β (THRB), impacting pathways related to programmed cell death and inflammation. As a workflow-oriented data analysis tool, ToxDAR is expected to be crucial for understanding toxic mechanisms from omics data, discovering new therapeutic targets, and evaluating chemical safety.
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Affiliation(s)
- Peng Jiang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Zuzhen Zhang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Qing Yu
- College of Life Sciences, Hebei University, Baoding 071002, China
| | - Ze Wang
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Lihong Diao
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Dong Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- College of Life Sciences, Hebei University, Baoding 071002, China
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
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Andersen JV, Schousboe A. Glial Glutamine Homeostasis in Health and Disease. Neurochem Res 2023; 48:1100-1128. [PMID: 36322369 DOI: 10.1007/s11064-022-03771-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 08/25/2022] [Accepted: 09/27/2022] [Indexed: 11/05/2022]
Abstract
Glutamine is an essential cerebral metabolite. Several critical brain processes are directly linked to glutamine, including ammonia homeostasis, energy metabolism and neurotransmitter recycling. Astrocytes synthesize and release large quantities of glutamine, which is taken up by neurons to replenish the glutamate and GABA neurotransmitter pools. Astrocyte glutamine hereby sustains the glutamate/GABA-glutamine cycle, synaptic transmission and general brain function. Cerebral glutamine homeostasis is linked to the metabolic coupling of neurons and astrocytes, and relies on multiple cellular processes, including TCA cycle function, synaptic transmission and neurotransmitter uptake. Dysregulations of processes related to glutamine homeostasis are associated with several neurological diseases and may mediate excitotoxicity and neurodegeneration. In particular, diminished astrocyte glutamine synthesis is a common neuropathological component, depriving neurons of an essential metabolic substrate and precursor for neurotransmitter synthesis, hereby leading to synaptic dysfunction. While astrocyte glutamine synthesis is quantitatively dominant in the brain, oligodendrocyte-derived glutamine may serve important functions in white matter structures. In this review, the crucial roles of glial glutamine homeostasis in the healthy and diseased brain are discussed. First, we provide an overview of cellular recycling, transport, synthesis and metabolism of glutamine in the brain. These cellular aspects are subsequently discussed in relation to pathological glutamine homeostasis of hepatic encephalopathy, epilepsy, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Further studies on the multifaceted roles of cerebral glutamine will not only increase our understanding of the metabolic collaboration between brain cells, but may also aid to reveal much needed therapeutic targets of several neurological pathologies.
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Affiliation(s)
- Jens V Andersen
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
| | - Arne Schousboe
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
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Shurubor YI, Rogozhin AE, Isakova EP, Deryabina YI, Krasnikov BF. Tricarboxylic Acid Metabolite Imbalance in Rats with Acute Thioacetamide-Induced Hepatic Encephalopathy Indicates Incomplete Recovery. Int J Mol Sci 2023; 24:ijms24021384. [PMID: 36674898 PMCID: PMC9861856 DOI: 10.3390/ijms24021384] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/20/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023] Open
Abstract
Exposure to the toxin thioacetamide (TAA) causes acute hepatic encephalopathy (HE), changes in the functioning of systemic organs, and an imbalance in a number of energy metabolites. The deferred effects after acute HE development are poorly understood. The study considers the balance of the tricarboxylic acid (TCA) cycle metabolites in the blood plasma, liver, kidneys, and brain tissues of rats in the post-rehabilitation period. The samples of the control (n = 3) and TAA-induced groups of rats (n = 13) were collected six days after the administration of a single intraperitoneal TAA injection at doses of 200, 400, and 600 mg/kg. Despite the complete physiological recovery of rats by this date, a residual imbalance of metabolites in all the vital organs was noted. The results obtained showed a trend of stabilizing processes in the main organs of the animals and permit the use of these data both for prognostic purposes and the choice of potential therapeutic agents.
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Affiliation(s)
- Yevgeniya I. Shurubor
- Centre for Strategic Planning and Management of Medical and Biological Health Risks, Federal Medical Biological Agency of The Russian Federation, Moscow 119121, Russia
| | - Alexander E. Rogozhin
- Valiev Institute of Physics and Technology of the Russian Academy of Sciences, Moscow 117218, Russia
| | - Elena P. Isakova
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia
| | - Yulia I. Deryabina
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russia
| | - Boris F. Krasnikov
- Centre for Strategic Planning and Management of Medical and Biological Health Risks, Federal Medical Biological Agency of The Russian Federation, Moscow 119121, Russia
- Correspondence: ; Tel.: +7-(985)-095-5445
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Kroupina K, Bémeur C, Rose CF. Amino acids, ammonia, and hepatic encephalopathy. Anal Biochem 2022; 649:114696. [PMID: 35500655 DOI: 10.1016/j.ab.2022.114696] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 03/30/2022] [Accepted: 04/21/2022] [Indexed: 11/30/2022]
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Cognitive Impairement in Non-Cirrhotic Portal Hypertension: Highlights on Physiopathology, Diagnosis and Management. J Clin Med 2021; 11:jcm11010101. [PMID: 35011842 PMCID: PMC8745274 DOI: 10.3390/jcm11010101] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/19/2021] [Accepted: 12/21/2021] [Indexed: 11/18/2022] Open
Abstract
Hepatic encephalopathy (HE) is one of the most frequent complications of cirrhosis. Several studies and case reports have shown that cognitive impairment may also be a tangible complication of portal hypertension secondary to chronic portal vein thrombosis and to porto-sinusoidal vascular disease (PSVD). In these conditions, representing the main causes of non-cirrhotic portal hypertension (NCPH) in the Western world, both overt and minimal/covert HE occurs in a non-neglectable proportion of patients, even lower than in cirrhosis, and it is mainly sustained by the presence of large porto-systemic shunt. In these patients, the liver function is usually preserved or only mildly altered, and the development of porto-systemic shunt is either spontaneous or iatrogenically frequent; HE is an example of type-B HE. To date, in the absence of strong evidence and large cooperative studies, for the diagnosis and the management of HE in NCPH, the same approach used for HE occurring in cirrhosis is applied. The aim of this paper is to provide an overview of type B hepatic encephalopathy, focusing on its pathophysiology, diagnostic tools and management in patients affected by porto-sinusoidal vascular disease and chronic portal vein thrombosis.
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Shurubor YI, Cooper AJL, Krasnikov AB, Isakova EP, Deryabina YI, Beal MF, Krasnikov BF. Changes of Coenzyme A and Acetyl-Coenzyme A Concentrations in Rats after a Single-Dose Intraperitoneal Injection of Hepatotoxic Thioacetamide Are Not Consistent with Rapid Recovery. Int J Mol Sci 2020; 21:E8918. [PMID: 33255464 PMCID: PMC7727790 DOI: 10.3390/ijms21238918] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022] Open
Abstract
Small biomolecules, such as coenzyme A (CoA) and acetyl coenzyme A (acetyl-CoA), play vital roles in the regulation of cellular energy metabolism. In this paper, we evaluated the delayed effect of the potent hepatotoxin thioacetamide (TAA) on the concentrations of CoA and acetyl-CoA in plasma and in different rat tissues. Administration of TAA negatively affects liver function and leads to the development of hepatic encephalopathy (HE). In our experiments, rats were administered a single intraperitoneal injection of TAA at doses of 200, 400, or 600 mg/kg. Plasma, liver, kidney, and brain samples were collected six days after the TAA administration, a period that has been suggested to allow for restoration of liver function. The concentrations of CoA and acetyl-CoA in the group of rats exposed to different doses of TAA were compared to those observed in healthy rats. The results obtained indicate that even a single administration of TAA to rats is sufficient to alter the physiological balance of CoA and acetyl-CoA in the plasma and tissues of rats for an extended period of time. The initial concentrations of CoA and acetyl-CoA were not restored even after the completion of the liver regeneration process.
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Affiliation(s)
- Yevgeniya I. Shurubor
- Center for Strategic Planning and Management of Medical and Biological Health Risks, Federal Medical-Biological Agency of The Russian Federation, 119121 Moscow, Russia;
| | - Arthur J. L. Cooper
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
| | | | - Elena P. Isakova
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia; (E.P.I.); (Y.I.D.)
| | - Yulia I. Deryabina
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia; (E.P.I.); (Y.I.D.)
| | - M. Flint Beal
- Department of Neurology, The Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021, USA;
| | - Boris F. Krasnikov
- Center for Strategic Planning and Management of Medical and Biological Health Risks, Federal Medical-Biological Agency of The Russian Federation, 119121 Moscow, Russia;
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
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Eslami Gharaati M, Nahavandi A, Baluchnejad Mojarad T, Roghani M. Diabetic Encephalopathy Affecting Mitochondria and Axonal Transport Proteins. Basic Clin Neurosci 2020; 11:781-793. [PMID: 33850615 PMCID: PMC8019849 DOI: 10.32598/bcn.11.6.1657.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 01/10/2019] [Accepted: 05/13/2019] [Indexed: 01/21/2023] Open
Abstract
Introduction Diabetic encephalopathy is described as any cognitive and memory impairments associated with hippocampal degenerative changes, including the neurodegenerative process and decreased number of living cells. Mitochondrial diabetes (MD) appears following activation of mutant mitochondrial DNA and is a combination of diabetes and cognitive deficit. In this research, we showed the correlation of diabetic encephalopathy, dysfunctional mitochondria, and changes in the expression of axonal transport proteins (KIF5b, Dynein). Methods Twenty-four male Wistar rats were divided into three groups: (n=8 in each group):1. Control + saline; 2. Diabetic, and 3. Diabetic + insulin. Before starting the experiments, the animals with blood sugar lower than 150 mg/dL entered the study. Diabetes induction was carried out by Intraperitoneal (IP) Streptozotocin (STZ) administration. Fasting Blood Sugar (FBS) and body weight was checked after the first week and at the end of the eighth week. Then, behavioral studies (elevated plus maze, Y-maze, and passive avoidance learning) were performed. After behavioral studies, blood samples were taken to measure serum insulin level and HgbA1c. Next, fresh hippocampal tissue was collected. Gene expression of motor proteins was assessed by real-time PCR and mitochondrial membrane potential by rhodamine123. Results Our results showed the impairment of HgbA1c, serum insulin, FBS, and weight in the diabetic group (P<0.05). Behavioral tests revealed different degrees of impairment in diabetic rats (P<0.05). KIF5b mRNA expression increased in the hippocampus (P<0.05) with no change in dynein gene expression. These changes were associated with abnormal mitochondrial membrane potential (P<0.05). Conclusion KIF5b mRNA up-regulation in hippocampal neurons of STZ-diabetic rats is a factor that can be involved in abnormal axonal transport and decreased MMP, leading to impairment of mitochondrial function. These manifestations showed mitochondrial dysfunction in diabetes and resulted in abnormal behavioral tests and diabetic encephalopathy.
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Affiliation(s)
- Maryam Eslami Gharaati
- Department of Physiology, School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Arezo Nahavandi
- Department of Physiology, School of Medicine, Iran University of Medical Science, Tehran, Iran.,Neuroscience Research Center, Iran University of Medical Science, Tehran, Iran
| | | | - Mehrdad Roghani
- Departmentof Physiology, Neurophysiology Research Center, Shahed University, Tehran, Iran
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Mohammadi H, Sayad A, Mohammadi M, Niknahad H, Heidari R. N-acetyl cysteine treatment preserves mitochondrial indices of functionality in the brain of hyperammonemic mice. Clin Exp Hepatol 2020; 6:106-115. [PMID: 32728627 PMCID: PMC7380475 DOI: 10.5114/ceh.2020.95814] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 02/20/2020] [Indexed: 12/11/2022] Open
Abstract
AIM OF THE STUDY Acute or chronic live failure could result in hyperammonemia and hepatic encephalopathy (HE). HE is a clinical complication characterized by severe cognitive dysfunction and coma. The ammonium ion (NH4 +) is the most suspected toxic molecule involved in the pathogenesis of HE. NH4 + is a neurotoxic agent. Different mechanisms, including oxidative/nitrosative stress, inflammatory response, excitotoxicity, and mitochondrial impairment, are proposed for NH4 +-induced neurotoxicity. N-acetyl cysteine (NAC) is a well-known thiol-reductant and antioxidant agent. Several investigations also mentioned the positive effects of NAC on mitochondrial function. In the current study, the effect of NAC treatment on brain mitochondrial indices and energy status was investigated in an animal model of HE. MATERIAL AND METHODS Acetaminophen (APAP)-induced acute liver failure was induced by a single dose of the drug (800 mg/kg, i.p.) to C57BL/6J mice. Plasma and brain levels of NH4 + were measured. Then, brain mitochondria were isolated, and several indices, including mitochondrial depolarization, ATP level, lipid peroxidation, glutathione content, mitochondrial permeabilization, and dehydrogenase activity, were assessed. RESULTS A significant increase in plasma and brain NH4 + was evident in APAP-treated animals. Moreover, mitochondrial indices of functionality were impaired, and mitochondrial oxidative stress biomarkers were significantly increased in APAP-treated mice. It was found that NAC treatment (100, 200, and 400 mg/kg, i.p.) significantly mitigated mitochondrial impairment in the brain of APAP-treated animals. CONCLUSIONS These data suggest the effects of NAC on brain mitochondrial function and energy status as a pivotal mechanism involved in its neuroprotective properties during HE.
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Affiliation(s)
- Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abolfazl Sayad
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Mohammadi
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Kerbert AJC, Jalan R. Recent advances in understanding and managing hepatic encephalopathy in chronic liver disease. F1000Res 2020; 9. [PMID: 32399191 PMCID: PMC7194462 DOI: 10.12688/f1000research.22183.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is a common, severe complication of advanced chronic liver disease (CLD) and has a devastating impact on the patient’s quality of life and prognosis. The neurotoxin ammonia and the presence of systemic and neurological inflammation are considered the key drivers of this neuropsychiatric syndrome. Treatment options available in routine clinical practice are limited, and the development of novel therapies is hampered owing to the complexity and heterogeneity of HE. This review article aims to outline the current understanding of the pathomechanisms of HE and the recent advances in the identification and development of novel therapeutic targets.
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Affiliation(s)
- Annarein J C Kerbert
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Rajiv Jalan
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
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Probst J, Kölker S, Okun JG, Kumar A, Gursky E, Posset R, Hoffmann GF, Peravali R, Zielonka M. Chronic hyperammonemia causes a hypoglutamatergic and hyperGABAergic metabolic state associated with neurobehavioral abnormalities in zebrafish larvae. Exp Neurol 2020; 331:113330. [PMID: 32339612 DOI: 10.1016/j.expneurol.2020.113330] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/29/2020] [Accepted: 04/23/2020] [Indexed: 12/13/2022]
Abstract
Chronic hyperammonemia is a common condition affecting individuals with inherited urea cycle disorders resulting in progressive cognitive impairment and behavioral abnormalities. Altered neurotransmission has been proposed as major source of neuronal dysfunction during chronic hyperammonemia, but the molecular pathomechanism has remained incompletely understood. Here we show that chronic exposure to ammonium acetate induces locomotor dysfunction and abnormal feeding behavior in zebrafish larvae, indicative for an impairment of higher brain functions. Biochemically, chronically elevated ammonium concentrations cause enhanced activity of glutamate decarboxylase isoforms GAD1 and GAD2 with increased formation of GABA and concomitant depletion of glutamate, ultimately leading to a dysfunctional hypoglutamatergic and hyperGABAergic metabolic state. Moreover, elevated GABA concentrations are accompanied by increased expression of GABAA receptor subunits alpha-1, gamma-2 and delta, supporting the notion of an increased GABA tone in chronic hyperammonemia. Propionate oxidation as major anaplerotic reaction sufficiently compensates for the transamination-dependent withdrawal of 2-oxoglutarate, thereby preventing bioenergetic dysfunction under chronic hyperammonemic conditions. Thus, our study extends the hypothesis of alterations in the glutamatergic and GABAergic system being an important pathophysiological factor causing neurobehavioral impairment in chronic hyperammonemia. Given that zebrafish larvae have already been successfully used for high-throughput identification of novel compounds to treat inherited neurological diseases, the reported zebrafish model should be considered an important tool for systematic drug screening targeting altered glutamatergic and GABAergic metabolism under chronic hyperammonemic conditions in the future.
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Affiliation(s)
- Joris Probst
- Center for Child and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Kölker
- Center for Child and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Jürgen G Okun
- Center for Child and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Amrish Kumar
- Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Eduard Gursky
- Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Roland Posset
- Center for Child and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Georg F Hoffmann
- Center for Child and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Ravindra Peravali
- Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany
| | - Matthias Zielonka
- Center for Child and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany; Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany.
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Guazzelli PA, Cittolin-Santos GF, Meira-Martins LA, Grings M, Nonose Y, Lazzarotto GS, Nogara D, da Silva JS, Fontella FU, Wajner M, Leipnitz G, Souza DO, de Assis AM. Acute Liver Failure Induces Glial Reactivity, Oxidative Stress and Impairs Brain Energy Metabolism in Rats. Front Mol Neurosci 2020; 12:327. [PMID: 31998076 PMCID: PMC6968792 DOI: 10.3389/fnmol.2019.00327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 12/18/2019] [Indexed: 01/02/2023] Open
Abstract
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.
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Affiliation(s)
- Pedro Arend Guazzelli
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Giordano Fabricio Cittolin-Santos
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Leo Anderson Meira-Martins
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Mateus Grings
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Yasmine Nonose
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Gabriel S Lazzarotto
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Daniela Nogara
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Jussemara S da Silva
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Fernanda U Fontella
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Moacir Wajner
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Guilhian Leipnitz
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Diogo O Souza
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Adriano Martimbianco de Assis
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Post-graduate Program in Health and Behavior, Health Sciences Centre, Universidade Católica de Pelotas-UCPel, Pelotas, Brazil
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14
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Bai Y, Wang S, Wu F, Xie X, Wang Y, Yang Y. The Changes of Mitochondria in Substantia Nigra and Anterior Cerebral Cortex of Hepatic Encephalopathy Induced by Thioacetamide. Anat Rec (Hoboken) 2019; 302:1169-1177. [PMID: 30290401 PMCID: PMC6899860 DOI: 10.1002/ar.23932] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 01/22/2018] [Accepted: 02/03/2018] [Indexed: 01/10/2023]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from chronic or acute liver failure. Under the condition of HE, various factors such as reactive oxygen species, inflammatory factors, ammonia poisoning and amino acids alteration lead to changes of mitochondria. Selective depletion of damaged mitochondrion is essential for maintaining the morphology and function of mitochondria and cells. In this study, molecular biology analysis was used to analyze the mitochondrial morphology in the substantia nigra (SN) and anterior cerebral cortex (ACC) of the HE mice. The results revealed that the drp1, mfn1 and mfn2 increased in mRNA level of SN, which indicated the changes of mitochondrial morphology in HE mice. The drp1 and mfn2 genes were up‐regulated, then, the Opa1 exhibited no significant change in the ACC of HE mice. Further study demonstrated that the mitochondrial autophagy related genes, pink1 and parkin, increased in SN, while the parkin reduced in ACC of HE mice. In addition, uncoupling protein (ucp2) increased in mRNA level of SN and ACC, and the ucp4 had no change or reduced in SN and ACC, respectively. These findings suggested that the mitochondrial dynamics is different in the SN and ACC of HE mice. Therefore, our results indicated that mitochondrial dynamics provided a potential treatment strategy for HE through the fission, fusion and autophagy of genes. Anat Rec, 302:1169–1177, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
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Affiliation(s)
- Yunhu Bai
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China.,Department of general surgery, People's Liberation Army's 153rd hospital, Zhengzhou, China
| | - Shengming Wang
- Department of Anatomy and K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, China
| | - Feifei Wu
- Department of Anatomy and K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, China
| | - Xiangjun Xie
- Department of Preventive Medicine, The Fourth Military Medical University, Xi'an, China
| | - Yayun Wang
- Department of Anatomy and K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, China
| | - Yanling Yang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
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15
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Lima LCD, Miranda AS, Ferreira RN, Rachid MA, Simões E Silva AC. Hepatic encephalopathy: Lessons from preclinical studies. World J Hepatol 2019; 11:173-185. [PMID: 30820267 PMCID: PMC6393717 DOI: 10.4254/wjh.v11.i2.173] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/19/2018] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a major complication that is closely related to the progression of end-stage liver disease. Metabolic changes in advanced liver failure can promote cognition impairment, attention deficits and motor dysfunction that may result in coma and death. HE can be subdivided according to the type of hepatic injury, namely, type A, which results from acute liver failure, type B, which is associated with a portosystemic shunting without intrinsic liver disease, and type C, which is due to chronic liver disease. Several studies have investigated the pathogenesis of the disease, and most of the mechanisms have been explored using animal models. This article aimed to review the use of preclinical models to investigate HE. The most used animal species are rats and mice. Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications, whereas models of types B and C HE are generally surgically induced lesions in liver tissue, which evolve to hepatic cirrhosis. Preclinical models have allowed the comprehension of the pathways related to HE.
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Affiliation(s)
- Luiza Cioglia Dias Lima
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brasil
| | - Aline Silva Miranda
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil
| | - Rodrigo Novaes Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil
| | - Milene Alvarenga Rachid
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brasil
| | - Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil.
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16
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Astrocytic pyruvate carboxylation: Status after 35 years. J Neurosci Res 2019; 97:890-896. [DOI: 10.1002/jnr.24402] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/11/2019] [Accepted: 02/05/2019] [Indexed: 12/24/2022]
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17
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Heidari R. Brain mitochondria as potential therapeutic targets for managing hepatic encephalopathy. Life Sci 2019; 218:65-80. [PMID: 30578865 DOI: 10.1016/j.lfs.2018.12.030] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/08/2018] [Accepted: 12/16/2018] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a critical clinical complication. There is a consensus that ammonia plays a pivotal role in the pathogenesis of HE. Ammonia is a neurotoxin which induces a wide range of functional disturbances in the central nervous system (CNS). On the other hand, HE is associated with the increased free radical formation, tissue inflammation, disturbed neurotransmission, astrocytes swelling, brain edema, and brain herniation. In view of the severe CNS complications ensued HE, potential therapeutic points of intervention need to be vigorously investigated. A role for CNS mitochondrial damage and energy crisis has been considered in HE. It has been found that ammonia induces mitochondrial impairment as a result of a multifaceted interaction of different signaling molecules. Hence, ammonia-induced mitochondrial injury and compromised brain energy metabolism might play a vital role in the pathogenesis of ammonia neurotoxicity. This review focuses on the concept that mitochondrial dysfunction and cellular energy crisis indeed plays a critical role in the pathogenesis of hyperammonemia-induced brain injury. Further, it will highlight the potential therapeutic value of mitochondrial protecting agents and energy providers in the management of HE. The data collected in this review might provide clues to new therapeutic interventions aimed at minimizing HE-associated complications.
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Affiliation(s)
- Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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18
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Zielonka M, Probst J, Carl M, Hoffmann GF, Kölker S, Okun JG. Bioenergetic dysfunction in a zebrafish model of acute hyperammonemic decompensation. Exp Neurol 2019; 314:91-99. [PMID: 30653968 DOI: 10.1016/j.expneurol.2019.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/18/2018] [Accepted: 01/12/2019] [Indexed: 12/30/2022]
Abstract
Acute hyperammonemic encephalopathy is a life-threatening manifestation of individuals with urea cycle disorders, which is associated with high mortality rates and severe neurological sequelae in survivors. Cerebral bioenergetic failure has been proposed as one of the key mechanisms underlying hyperammonemia-induced brain damage, but data supporting this hypothesis remain inconclusive and partially contradictory. Using a previously established zebrafish model of acute hyperammonemic decompensation, we unraveled that acute hyperammonemia leads to a transamination-dependent withdrawal of 2-oxoglutarate (alpha-ketoglutarate) from the tricarboxylic acid (TCA) cycle with consecutive TCA cycle dysfunction, ultimately causing impaired oxidative phosphorylation with ATP shortage, decreased ATP/ADP-ratio and elevated lactate concentrations. Thus, our study supports and extends the hypothesis that cerebral bioenergetic dysfunction is an important pathophysiological hallmark of hyperammonemia-induced neurotoxicity.
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Affiliation(s)
- Matthias Zielonka
- Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany; Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany.
| | - Joris Probst
- Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias Carl
- Center for Integrative Biology (CIBIO), Laboratory of Translational Neurogenetics, University of Trento, Trento, Italy
| | - Georg Friedrich Hoffmann
- Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Kölker
- Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Jürgen Günther Okun
- Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany
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19
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Takikawa Y, Sato T, Kakisaka K. Hepatic Encephalopathy in Liver Cirrhosis. THE EVOLVING LANDSCAPE OF LIVER CIRRHOSIS MANAGEMENT 2019:93-103. [DOI: 10.1007/978-981-13-7979-6_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Gelfand NA, Fedorenko EV, Mirochnik AG, Vovna VI. Interaction of hydroxy substituted dibenzoylmethanatoboron difluoride with hydrated ammonia in solution: A combined spectroscopic and computational study. J Mol Struct 2019. [DOI: 10.1016/j.molstruc.2018.08.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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21
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Veskoukis AS, Margaritelis NV, Kyparos A, Paschalis V, Nikolaidis MG. Spectrophotometric assays for measuring redox biomarkers in blood and tissues: the NADPH network. Redox Rep 2018; 23:47-56. [PMID: 29088980 PMCID: PMC6748689 DOI: 10.1080/13510002.2017.1392695] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+/NADH) along with its phosphorylated form (NADP+/NADPH) are two molecules ubiquitously present in all organisms, and they play key roles as cofactors in fundamental catabolic and anabolic processes, respectively. The oxidation of NADPH to NADP+ initiates a cascade of reactions, where a network of molecules is implicated. The molecules of this cascade form a network with eminent translational potential in redox metabolism. A special point of interest is that spectrophotometric assays have been developed both for NADH/NADPH and the molecules directly regulated by them. Therefore, crucial molecules of the NADPH-dependent redox network can be measured, and the results can be used to assess the bioenergetic and/or oxidative stress status. The main aim of this review is to collectively present the NADPH-related molecules, namely NADPH, NADH, NAD+ kinase, NADPH oxidase, peroxiredoxin, thioredoxin, thioredoxin reductase, and nitric oxide synthase, that can be measured in blood and tissues with the use of a spectrophotometer, which is probably the most simple, inexpensive and widely used tool in biochemistry. We are providing the researchers with reliable and valid spectrophotometric assays for the measurement of the most important biomarkers of the NADPH network in blood and other tissues, thus allowing the opportunity to follow the redox changes in response to a stimulus.
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Affiliation(s)
- Aristidis S. Veskoukis
- Department of Biochemistry and
Biotechnology, University of Thessaly, Larissa,
Greece
- Department of Physical Education and
Sports Science at Serres, Aristotle University of
Thessaloniki, Serres, Greece
| | - Nikos V. Margaritelis
- Department of Physical Education and
Sports Science at Serres, Aristotle University of
Thessaloniki, Serres, Greece
- Intensive Care Unit, 424 General Military
Hospital of Thessaloniki, Thessaloniki,
Greece
| | - Antonios Kyparos
- Department of Physical Education and
Sports Science at Serres, Aristotle University of
Thessaloniki, Serres, Greece
| | - Vassilis Paschalis
- School of Physical Education and Sport
Science, National and Kapodistrian University of Athens,
Athens, Greece
- Department of Health Sciences, School of
Sciences, European University Cyprus, Nicosia,
Cyprus
| | - Michalis G. Nikolaidis
- Department of Physical Education and
Sports Science at Serres, Aristotle University of
Thessaloniki, Serres, Greece
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22
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Affiliation(s)
- Z.Q. Shi
- Artificial Cells and Organs Research Centre Faculty of Medicine, Mc Gill University 3655 Drummond Street, Montreal, Canada H3G 1Y6
| | - T.M.S. Chang
- Artificial Cells and Organs Research Centre Faculty of Medicine, Mc Gill University 3655 Drummond Street, Montreal, Canada H3G 1Y6
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23
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Kosenko EA, Tikhonova LA, Alilova GA, Montoliu C, Barreto GE, Aliev G, Kaminsky YG. Portacaval shunting causes differential mitochondrial superoxide production in brain regions. Free Radic Biol Med 2017; 113:109-118. [PMID: 28964916 DOI: 10.1016/j.freeradbiomed.2017.09.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 09/08/2017] [Accepted: 09/25/2017] [Indexed: 01/23/2023]
Abstract
The portacaval shunting (PCS) prevents portal hypertension and recurrent bleeding of esophageal varices. On the other hand, it can induce chronic hyperammonemia and is considered to be the best model of mild hepatic encephalopathy (HE). Pathogenic mechanisms of HE and dysfunction of the brain in hyperammonemia are not fully elucidated, but it was originally suggested that the pathogenetic defect causes destruction of antioxidant defense which leads to an increase in the production of reactive oxygen species (ROS) and the occurrence of oxidative stress. In order to gain insight into the pathogenic mechanisms of HE in the brain tissue, we investigated the effects of PCS in rats on free radicals production and activity levels of antioxidant and prooxidant enzymes in mitochondria isolated from different brain areas. We found that O2·- production, activities of Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione transferase (GT), nitric oxide synthase (NOS), and levels of carbonylated proteins differed between the four brain regions both in the amount and response to PCS. In PCS rats, Mn-SOD activity in the cerebellum was significantly decreased, and remained unchanged in the neocortex, hippocampus and striatum compared with that in sham-operated animals. Among the four brain regions in control rats, the levels of the carbonyl groups in mitochondrial proteins were maximal in the cerebellum. 4 weeks after PCS, the content of carbonylated proteins were higher only in mitochondria of this brain region. Under control conditions, O2·- production by submitochondrial particles in the cerebellum was significantly higher than in other brain regions, but was significantly increased in each brain region from PCS animals. Indeed, the production of O2·- by submitochondrial particles correlated with mitochondrial ammonia levels in the four brain regions of control and PCS-animals. These findings are the first to suggest that in vivo levels of ammonia in the brain directly affect the rate of mitochondrial O2·- production.
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Affiliation(s)
- Elena A Kosenko
- Institute of Theoretical and Experimental Biophysics, Pushchino, Russia.
| | | | - Gubidat A Alilova
- Institute of Theoretical and Experimental Biophysics, Pushchino, Russia
| | - Carmina Montoliu
- Fundación Investigación Hospital Clínico, Instituto Investigación Sanitaria-INCLIVA, Valencia, Spain
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Gjumrakch Aliev
- GALLY International Biomedical Research Institute Inc., 7733 Louis Pasteur Drive, #330, San Antonio, TX 78229, USA; School of Health Science and Healthcare Administration, University of Atlanta, E. Johns Crossing, #175, Johns Creek, GA 30097, USA.
| | - Yury G Kaminsky
- Institute of Theoretical and Experimental Biophysics, Pushchino, Russia
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24
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Lanz B, Rackayova V, Braissant O, Cudalbu C. MRS studies of neuroenergetics and glutamate/glutamine exchange in rats: Extensions to hyperammonemic models. Anal Biochem 2017; 529:245-269. [DOI: 10.1016/j.ab.2016.11.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 11/16/2016] [Accepted: 11/30/2016] [Indexed: 01/27/2023]
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25
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Krasnikov BF, Deryabina YI, Isakova EP, Biriukova IK, Shevelev AB, Antipov AN. New recombinant producer of human ω-amidase based on Escherichia coli. APPL BIOCHEM MICRO+ 2017. [DOI: 10.1134/s0003683817030115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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26
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Hertz L, Rothman DL. Glutamine-Glutamate Cycle Flux Is Similar in Cultured Astrocytes and Brain and Both Glutamate Production and Oxidation Are Mainly Catalyzed by Aspartate Aminotransferase. BIOLOGY 2017; 6:biology6010017. [PMID: 28245547 PMCID: PMC5372010 DOI: 10.3390/biology6010017] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 02/06/2017] [Accepted: 02/14/2017] [Indexed: 01/15/2023]
Abstract
The glutamine-glutamate cycle provides neurons with astrocyte-generated glutamate/γ-aminobutyric acid (GABA) and oxidizes glutamate in astrocytes, and it returns released transmitter glutamate/GABA to neurons after astrocytic uptake. This review deals primarily with the glutamate/GABA generation/oxidation, although it also shows similarity between metabolic rates in cultured astrocytes and intact brain. A key point is identification of the enzyme(s) converting astrocytic α-ketoglutarate to glutamate and vice versa. Most experiments in cultured astrocytes, including those by one of us, suggest that glutamate formation is catalyzed by aspartate aminotransferase (AAT) and its degradation by glutamate dehydrogenase (GDH). Strongly supported by results shown in Table 1 we now propose that both reactions are primarily catalyzed by AAT. This is possible because the formation occurs in the cytosol and the degradation in mitochondria and they are temporally separate. High glutamate/glutamine concentrations abolish the need for glutamate production from α-ketoglutarate and due to metabolic coupling between glutamate synthesis and oxidation these high concentrations render AAT-mediated glutamate oxidation impossible. This necessitates the use of GDH under these conditions, shown by insensitivity of the oxidation to the transamination inhibitor aminooxyacetic acid (AOAA). Experiments using lower glutamate/glutamine concentration show inhibition of glutamate oxidation by AOAA, consistent with the coupled transamination reactions described here.
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Affiliation(s)
- Leif Hertz
- Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Liaoning 110000, China.
| | - Douglas L Rothman
- Magnetic Resonance Research Center, Radiology and Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
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27
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Cruz NF, Dienel GA, Patrick PA, Cooper AJL. Organ Distribution of 13N Following Intravenous Injection of [ 13N]Ammonia into Portacaval-Shunted Rats. Neurochem Res 2016; 42:1683-1696. [PMID: 27822667 DOI: 10.1007/s11064-016-2096-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 10/27/2016] [Accepted: 10/31/2016] [Indexed: 12/18/2022]
Abstract
Ammonia is neurotoxic, and chronic hyperammonemia is thought to be a major contributing factor to hepatic encephalopathy in patients with liver disease. Portacaval shunting of rats is used as an animal model to study the detrimental metabolic effects of elevated ammonia levels on body tissues, particularly brain and testes that are deleteriously targeted by high blood ammonia. In normal adult rats, the initial uptake of label (expressed as relative concentration) in these organs was relatively low following a bolus intravenous injection of [13N]ammonia compared with lungs, kidneys, liver, and some other organs. The objective of the present study was to determine the distribution of label following intravenous administration of [13N]ammonia among 14 organs in portacaval-shunted rats at 12 weeks after shunt construction. At an early time point (12 s) following administration of [13N]ammonia the relative concentration of label was highest in lung with lower, but still appreciable relative concentrations in kidney and heart. Clearance of 13N from blood and kidney tended to be slower in portacaval-shunted rats versus normal rats during the 2-10 min interval after the injection. At later times post injection, brain and testes tended to have higher-than-normal 13N levels, whereas many other tissues had similar levels in both groups. Thus, reduced removal of ammonia from circulating blood by the liver diverts more ammonia to extrahepatic tissues, including brain and testes, and alters the nitrogen homeostasis in these tissues. These results emphasize the importance of treatment paradigms designed to reduce blood ammonia levels in patients with liver disease.
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Affiliation(s)
- Nancy F Cruz
- Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Gerald A Dienel
- Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM, USA
| | | | - Arthur J L Cooper
- Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA.
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28
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Neurotoxicity of Ammonia. Neurochem Res 2016; 42:713-720. [PMID: 27465396 DOI: 10.1007/s11064-016-2014-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 07/15/2016] [Accepted: 07/21/2016] [Indexed: 12/25/2022]
Abstract
Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profoundly with brain metabolism, astrocyte volume regulation, and in particular mitochondrial functions. Gene expression in the brain and excitatory and inhibitory neurotransmission circuits are also affected. Experiments with a number of pertinent animal models have revealed several potential mechanisms which could underlie the pathological phenomena occurring in hepatic encephalopathy.
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Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity. Neurochem Res 2016; 42:721-736. [PMID: 27286679 DOI: 10.1007/s11064-016-1966-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 05/20/2016] [Accepted: 05/24/2016] [Indexed: 12/12/2022]
Abstract
Effects of ammonia on astrocytes play a major role in hepatic encephalopathy, acute liver failure and other diseases caused by increased arterial ammonia concentrations (e.g., inborn errors of metabolism, drug or mushroom poisoning). There is a direct correlation between arterial ammonia concentration, brain ammonia level and disease severity. However, the pathophysiology of hyperammonemic diseases is disputed. One long recognized factor is that increased brain ammonia triggers its own detoxification by glutamine formation from glutamate. This is an astrocytic process due to the selective expression of the glutamine synthetase in astrocytes. A possible deleterious effect of the resulting increase in glutamine concentration has repeatedly been discussed and is supported by improvement of some pathologic effects by GS inhibition. However, this procedure also inhibits a large part of astrocytic energy metabolism and may prevent astrocytes from responding to pathogenic factors. A decrease of the already low glutamate concentration in astrocytes due to increased synthesis of glutamine inhibits the malate-aspartate shuttle and energy metabolism. A more recently described pathogenic factor is the resemblance between NH4+ and K+ in their effects on the Na+,K+-ATPase and the Na+,K+, 2 Cl- and water transporter NKCC1. Stimulation of the Na+,K+-ATPase driven NKCC1 in both astrocytes and endothelial cells is essential for the development of brain edema. Na+,K+-ATPase stimulation also activates production of endogenous ouabains. This leads to oxidative and nitrosative damage and sensitizes NKCC1. Administration of ouabain antagonists may accordingly have therapeutic potential in hyperammonemic diseases.
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Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain. Biomolecules 2016; 6:biom6020016. [PMID: 27023624 PMCID: PMC4919911 DOI: 10.3390/biom6020016] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 03/10/2016] [Accepted: 03/15/2016] [Indexed: 12/21/2022] Open
Abstract
Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low—typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Here, we suggest that glutamate may constitute a buffer or bulwark against changes in cerebral amine and ammonia nitrogen. Although the glutamate transporters are briefly discussed, the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. Emphasis will also be placed on the central role of glutamate in the glutamine-glutamate and glutamine-GABA neurotransmitter cycles between neurons and astrocytes. Finally, we provide a brief and selective discussion of neuropathology associated with altered cerebral glutamate levels.
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Takeda K, Takemasa T. Expression of ammonia transporters Rhbg and Rhcg in mouse skeletal muscle and the effect of 6-week training on these proteins. Physiol Rep 2015; 3:3/10/e12596. [PMID: 26471760 PMCID: PMC4632962 DOI: 10.14814/phy2.12596] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The purposes of our study were to examine (1) Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg) expressions in mouse skeletal muscle; and (2) the effect of 6-week training on Rhbg and Rhcg expressions. The levels of Rhbg and Rhcg expressions were much higher in the soleus (Sol) than in the plantaris (Pla) or gastrocnemius (Gas). Immunofluorescence microscopy demonstrated that Rhbg colocalizes with dystrophin, a plasma membrane protein marker, whereas Rhcg colocalizes with CD31, a vascular endothelial cell marker. In a 6-week swim training study, we set up two different training groups. Endurance (END) group underwent swim training without load for 30 min and exercise time was increased by 30 min every 2 weeks. High-intensity interval training (HIIT) group underwent 10–12 sets of swim training at 20 sec per set and intervals of 10 sec, with a load of 10% body weight. After 6 weeks of training, all mice performed exhaustive swimming performance test (PT), with 9% of body weight to exhaustion. HIIT group could significantly swim more and showed significantly lower blood ammonia level compared with control (CON) group at immediately after PT. Rhbg and Rhcg levels did not change after 6 weeks in both END and HIIT groups. Our results indicate that ammonia transporters are more abundant in slow fiber than fast fiber muscles and 6 weeks swim training suppresses blood ammonia elevation induced by high-intensity exercise with performance improvement, although the levels of ammonia transporter proteins does not change.
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Affiliation(s)
- Kohei Takeda
- Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
| | - Tohru Takemasa
- Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
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Dienel GA, Cruz NF. Reduced clearance of proteins labeled with diisopropylfluorophosphate in portacaval-shunted rats. Metab Brain Dis 2014; 29:1041-52. [PMID: 24154686 PMCID: PMC4000281 DOI: 10.1007/s11011-013-9442-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 10/16/2013] [Indexed: 10/26/2022]
Abstract
Portacaval shunting is a model for hepatic encephalopathy that causes chronic hyperammonemia, disruption of metabolic, signaling, and neurotransmitter systems, and progressive morphological changes. Exposure of cultured cells to ammonia raises intralysosomal pH and inhibits proteolysis, and the present study tested the hypothesis that proteolytic capacity is diminished in portacaval-shunted rats. Proteins were labeled in vivo with tracer doses of diisopropylfluorophosphate (DFP) and clearance of label was assayed. This approach labeled proteins independent of protein synthesis, which is reported to be altered in shunted rats, and avoided complications arising from re-utilization of labeled amino acids that causes underestimation of degradation rate. Characterization of DFP labeling showed that protein labeling was fast, about 50% of the label was released during a 24 h interval, labeling by DFP metabolites was negligible, inhibition of brain acetylcholinesterase was not detectable, and labeling by [(3)H]- and [(14)C]DFP was equivalent. To assay degradative capacity, proteins were first labeled with [(3)H]DFP, followed by labeling with [(14)C]DFP that was given 24 or 72 h later. The (3)H/(14)C ratio in each animal was used as a relative measure of removal of (3)H-labeled proteins. (3)H/(14)C ratios were generally significantly higher in portacaval-shunted rats than in controls, consistent with reduced proteolytic capacity. Assays of amino acid incorporation into brain protein generally replicated literature reports, supporting the conclusion that protein synthesis unlikely to be markedly inhibited and amino acid recycling influences calculated protein synthesis rates in shunted rats. Therapeutic strategies to reduce ammonia level would help normalize lysosomal functions and protein and lipid turnover.
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Affiliation(s)
- Gerald A Dienel
- Department of Neurology, University of Arkansas for Medical Sciences, Slot 500, 4301 W. Markham St., Shorey Bldg., Room 715, Little Rock, AR, 72205, USA,
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Schousboe A, Waagepetersen HS, Leke R, Bak LK. Effects of hyperammonemia on brain energy metabolism: controversial findings in vivo and in vitro. Metab Brain Dis 2014; 29:913-7. [PMID: 24577633 DOI: 10.1007/s11011-014-9513-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 02/14/2014] [Indexed: 12/21/2022]
Abstract
The literature related to the effects of elevated plasma ammonia levels on brain energy metabolism is abundant, but heterogeneous in terms of the conclusions. Thus, some studies claim that ammonia has a direct, inhibitory effect on energy metabolism whereas others find no such correlation. In this review, we discuss both recent and older literature related to this controversial topic. We find that it has been consistently reported that hepatic encephalopathy and concomitant hyperammonemia lead to reduced cerebral oxygen consumption. However, this may not be directly linked to an effect of ammonia but related to the fact that hepatic encephalopathy is always associated with reduced brain activity, a condition clearly characterized by a decreased CMRO2. Whether this may be related to changes in GABAergic function remains to be elucidated.
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Affiliation(s)
- Arne Schousboe
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen Ø, Denmark
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Bosoi CR, Rose CF. Elevated cerebral lactate: Implications in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 2014; 29:919-25. [PMID: 24916505 DOI: 10.1007/s11011-014-9573-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 05/28/2014] [Indexed: 01/31/2023]
Abstract
Hepatic encephalopathy (HE), a complex neuropsychiatric syndrome, is a frequent complication of liver failure/disease. Increased concentrations of lactate are commonly observed in HE patients, in the systemic circulation, but also in the brain. Traditionally, increased cerebral lactate is considered a marker of energy failure/impairment however alterations in lactate homeostasis may also lead to a rise in brain lactate and result in neuronal dysfunction. The latter may involve the development of brain edema. This review will target the significance of increased cerebral lactate in the pathogenesis of HE.
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Affiliation(s)
- Cristina R Bosoi
- Hepato-Neuro Laboratory, Centre Hospitalier de l'Université de Montréal (CRCHUM), 900, rue Saint-Denis - Tour Viger R08.422, Québec, H2X 0A9, Canada,
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Abstract
Human adults produce around 1000 mmol of ammonia daily. Some is reutilized in biosynthesis. The remainder is waste and neurotoxic. Eventually most is excreted in urine as urea, together with ammonia used as a buffer. In extrahepatic tissues, ammonia is incorporated into nontoxic glutamine and released into blood. Large amounts are metabolized by the kidneys and small intestine. In the intestine, this yields ammonia, which is sequestered in portal blood and transported to the liver for ureagenesis, and citrulline, which is converted to arginine by the kidneys. The amazing developments in NMR imaging and spectroscopy and molecular biology have confirmed concepts derived from early studies in animals and cell cultures. The processes involved are exquisitely tuned. When they are faulty, ammonia accumulates. Severe acute hyperammonemia causes a rapidly progressive, often fatal, encephalopathy with brain edema. Chronic milder hyperammonemia causes a neuropsychiatric illness. Survivors of severe neonatal hyperammonemia have structural brain damage. Proposed explanations for brain edema are an increase in astrocyte osmolality, generally attributed to glutamine accumulation, and cytotoxic oxidative/nitrosative damage. However, ammonia neurotoxicity is multifactorial, with disturbances also in neurotransmitters, energy production, anaplerosis, cerebral blood flow, potassium, and sodium. Around 90% of hyperammonemic patients have liver disease. Inherited defects are rare. They are being recognized increasingly in adults. Deficiencies of urea cycle enzymes, citrin, and pyruvate carboxylase demonstrate the roles of isolated pathways in ammonia metabolism. Phenylbutyrate is used routinely to treat inherited urea cycle disorders, and its use for hepatic encephalopathy is under investigation.
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Affiliation(s)
- Valerie Walker
- Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
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Montana V, Verkhratsky A, Parpura V. Pathological role for exocytotic glutamate release from astrocytes in hepatic encephalopathy. Curr Neuropharmacol 2014; 12:324-33. [PMID: 25342940 PMCID: PMC4207072 DOI: 10.2174/1570159x12666140903094700] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 05/18/2014] [Accepted: 05/25/2014] [Indexed: 12/30/2022] Open
Abstract
Liver failure can lead to generalized hyperammonemia, which is thought to be the underlying cause of hepatic encephalopathy. This neuropsychiatric syndrome is accompanied by functional changes of astrocytes. These glial cells enter ammonia-induced self-amplifying cycle characterized by brain oedema, oxidative and osmotic stress that causes modification of proteins and RNA. Consequently, protein expression and function are affected, including that of glutamine synthetase and plasmalemmal glutamate transporters, leading to glutamate excitotoxicity; Ca2+-dependent exocytotic glutamate release from astrocytes contributes to this extracellular glutamate overload.
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Affiliation(s)
- Vedrana Montana
- Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy & Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain Institute, University of Alabama, Birmingham, AL 35294, USA ; Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
| | - Alexei Verkhratsky
- Faculty of Life Sciences, The University of Manchester, Manchester, M13 9PT, UK ; Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain ; University of Nizhny Novgorod, Nizhny Novgorod 603022, Russia
| | - Vladimir Parpura
- Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy & Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain Institute, University of Alabama, Birmingham, AL 35294, USA ; Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
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Haack N, Dublin P, Rose CR. Dysbalance of astrocyte calcium under hyperammonemic conditions. PLoS One 2014; 9:e105832. [PMID: 25153709 PMCID: PMC4143319 DOI: 10.1371/journal.pone.0105832] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 07/28/2014] [Indexed: 12/21/2022] Open
Abstract
Increased brain ammonium (NH4+/NH3) plays a central role in the manifestation of hepatic encephalopathy (HE), a complex syndrome associated with neurological and psychiatric alterations, which is primarily a disorder of astrocytes. Here, we analysed the influence of NH4+/NH3 on the calcium concentration of astrocytes in situ and studied the underlying mechanisms of NH4+/NH3-evoked calcium changes, employing fluorescence imaging with Fura-2 in acute tissue slices derived from different regions of the mouse brain. In the hippocampal stratum radiatum, perfusion with 5 mM NH4+/NH3 for 30 minutes caused a transient calcium increase in about 40% of astrocytes lasting about 10 minutes. Furthermore, the vast majority of astrocytes (∼90%) experienced a persistent calcium increase by ∼50 nM. This persistent increase was already evoked at concentrations of 1–2 mM NH4+/NH3, developed within 10–20 minutes and was maintained as long as the NH4+/NH3 was present. Qualitatively similar changes were observed in astrocytes of different neocortical regions as well as in cerebellar Bergmann glia. Inhibition of glutamine synthetase resulted in significantly larger calcium increases in response to NH4+/NH3, indicating that glutamine accumulation was not a primary cause. Calcium increases were not mimicked by changes in intracellular pH. Pharmacological inhibition of voltage-gated sodium channels, sodium-potassium-chloride-cotransporters (NKCC), the reverse mode of sodium/calcium exchange (NCX), AMPA- or mGluR5-receptors did not dampen NH4+/NH3-induced calcium increases. They were, however, significantly reduced by inhibition of NMDA receptors and depletion of intracellular calcium stores. Taken together, our measurements show that sustained exposure to NH4+/NH3 causes a sustained increase in intracellular calcium in astrocytes in situ, which is partly dependent on NMDA receptor activation and on release of calcium from intracellular stores. Our study furthermore suggests that dysbalance of astrocyte calcium homeostasis under hyperammonemic conditions is a widespread phenomenon, which might contribute to the disturbance of neurotransmission during HE.
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Affiliation(s)
- Nicole Haack
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Duesseldorf, Germany
| | - Pavel Dublin
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Duesseldorf, Germany
| | - Christine R. Rose
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Duesseldorf, Germany
- * E-mail:
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Increased brain lactate is central to the development of brain edema in rats with chronic liver disease. J Hepatol 2014; 60:554-60. [PMID: 24512824 DOI: 10.1016/j.jhep.2013.10.011] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 10/04/2013] [Accepted: 10/11/2013] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS The pathogenesis of brain edema in patients with chronic liver disease (CLD) and minimal hepatic encephalopathy (HE) remains undefined. This study evaluated the role of brain lactate, glutamine and organic osmolytes, including myo-inositol and taurine, in the development of brain edema in a rat model of cirrhosis. METHODS Six-week bile-duct ligated (BDL) rats were injected with (13)C-glucose and de novo synthesis of lactate, and glutamine in the brain was quantified using (13)C nuclear magnetic resonance spectroscopy (NMR). Total brain lactate, glutamine, and osmolytes were measured using (1)H NMR or high performance liquid chromatography. To further define the interplay between lactate, glutamine and brain edema, BDL rats were treated with AST-120 (engineered activated carbon microspheres) and dichloroacetate (DCA: lactate synthesis inhibitor). RESULTS Significant increases in de novo synthesis of lactate (1.6-fold, p<0.001) and glutamine (2.2-fold, p<0.01) were demonstrated in the brains of BDL rats vs. SHAM-operated controls. Moreover, a decrease in cerebral myo-inositol (p<0.001), with no change in taurine, was found in the presence of brain edema in BDL rats vs. controls. BDL rats treated with either AST-120 or DCA showed attenuation in brain edema and brain lactate. These two treatments did not lead to similar reductions in brain glutamine. CONCLUSIONS Increased brain lactate, and not glutamine, is a primary player in the pathogenesis of brain edema in CLD. In addition, alterations in the osmoregulatory response may also be contributing factors. Our results suggest that inhibiting lactate synthesis is a new potential target for the treatment of HE.
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Abstract
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis in alcoholic patients that is characterized clinically by personality changes, sleep abnormalities, and impaired motor coordination, as well as cognitive dysfunction progressing to stupor and coma. Procedures used for diagnosis and grading of HE include neurologic assessment, electroencephalography, psychometric testing, and use of the critical flicker frequency test. Neuropathologically, HE in cirrhosis is principally a disorder of neuroglia characterized by Alzheimer type II astrocytosis and activation of microglia. However, thalamic and cerebellar neuronal pathologies have been noted as well as lesions to globus pallidus and substantia nigra, leading to a condition known as "parkinsonism in cirrhosis." Multiple mechanisms have been proposed to account for the pathogenesis of HE in cirrhosis, including the neurotoxic actions of ammonia and manganese (normally removed via the hepatobiliary route), impaired brain energy metabolism, central proinflammatory mechanisms, and alterations of both excitatory and inhibitory neurotransmission. Treatment of HE in cirrhosis continues to rely on ammonia-lowering strategies such as lactulose, antibiotics, probiotics and l-ornithine l-aspartate with nutritional management consisting of adequate (but not excessive) dietary protein and vitamin B1 supplements. l-DOPA may improve parkinsonian symptoms. Liver transplantation leads to recovery of central nervous system function in the majority of cases.
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Affiliation(s)
- Roger F Butterworth
- Neuroscience Research Unit, Hôpital St-Luc (CHUM), University of Montreal, Montreal, Qc., Canada.
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Scott TR, Kronsten VT, Hughes RD, Shawcross DL. Pathophysiology of cerebral oedema in acute liver failure. World J Gastroenterol 2013; 19:9240-9255. [PMID: 24409052 PMCID: PMC3882398 DOI: 10.3748/wjg.v19.i48.9240] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 10/28/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
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.
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Bak LK, Waagepetersen HS, Sørensen M, Ott P, Vilstrup H, Keiding S, Schousboe A. Role of branched chain amino acids in cerebral ammonia homeostasis related to hepatic encephalopathy. Metab Brain Dis 2013; 28:209-15. [PMID: 23371316 DOI: 10.1007/s11011-013-9381-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Accepted: 01/17/2013] [Indexed: 12/30/2022]
Abstract
Hepatic encephalopathy (HE) is associated with increased ammonia levels in plasma and brain. Different treatment strategies have been developed to ameliorate the detrimental effects of the ammonia load. One such strategy is based on the finding of a low level of the branched chain amino acids (BCAAs) in plasma of patients suffering from HE and the assumption that in particular isoleucine could be beneficial to brain energy metabolism as it is metabolized to the tricarboxylic acid cycle intermediate and precursor succinyl-CoA and acetyl-CoA, respectively. This would enable de novo synthesis of glutamine via α-ketoglutarate and glutamate and at the same time stimulate oxidative metabolism. The present mini-review summarizes the metabolic basis for this hypothesis delineating studies in the brain in vivo as well as in cultured neural cells aimed at elucidating the metabolism of the BCAAs focusing on isoleucine. The conclusion is that isoleucine appears at least partially to act in this fashion albeit its metabolism is quantitatively relatively modest. In addition, a short section on the role of the BCAAs in synaptic ammonia homeostasis is included along with some thoughts on the role of the BCAAs in other pathologies such as cancer.
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Affiliation(s)
- Lasse K Bak
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.
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Sinha AK, Giblen T, AbdElgawad H, De Rop M, Asard H, Blust R, De Boeck G. Regulation of amino acid metabolism as a defensive strategy in the brain of three freshwater teleosts in response to high environmental ammonia exposure. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2013; 130-131:86-96. [PMID: 23384996 DOI: 10.1016/j.aquatox.2013.01.003] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Revised: 01/07/2013] [Accepted: 01/08/2013] [Indexed: 05/12/2023]
Abstract
Many teleosts have evolved mechanisms to cope with ammonia toxicity in the brain when confronted with high environmental ammonia (HEA). In the present study, the possible role of conversion of accumulated ammonia to glutamine and other free amino acids in the brain of three freshwater teleosts differing in their sensitivities to ammonia was investigated. The detoxification mode of ammonia in brain is suggested to be through amination of glutamate to glutamine by the coupled activities of glutamate dehydrogenase (GDH), transaminase (aspartate aminotransaminase 'AST' and alanine aminotransaminase 'ALT') and glutamine synthetase (GSase). We investigated the metabolic response of amino acids in the brain of highly sensitive salmonid Oncorhynchus mykiss (rainbow trout), the less sensitive cyprinid Cyprinus carpio (common carp) and the highly resistant cyprinid Carassius auratus (goldfish) when exposed to 1mM ammonia (as NH4HCO3; pH 7.9) for 0 h (control), 3 h, 12 h, 24 h, 48 h, 84 h and 180 h. Results show that HEA exposure increased ammonia accumulation significantly in the brain of all the three species from 12h onwards. Unlike in trout, ammonia accumulation in carp and goldfish was restored to control levels (48-84h); which was accompanied with a significant increase in glutamine content as well as GSase activity. In trout, glutamine levels also increased (84-180 h) but GSase was not activated. The elevated glutamine level in trout was accompanied by a significant depletion of the glutamate pool in contrast to the stable glutamate levels seen in carp and goldfish. This suggests a simultaneous increase in the rate of glutamate formation to match with the demand of glutamine formation in cyprinids. The activity of GDH was elevated significantly in carp and goldfish but remained unaltered in trout. Also, the transaminase enzymes (AST and ALT) were elevated significantly in exposed carp and goldfish while only ALT was up-regulated in trout. Consequently, in carp and goldfish both aspartate and alanine were utilized under HEA, whereas only alanine was consumed in trout. With ammonia treatment, significant changes in concentrations of other amino acids also occurred. None of the species could detoxify brain ammonia into urea. This study suggests that protective strategies to combat ammonia toxicity in brain are more pronounced in carp and goldfish than in trout.
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Affiliation(s)
- Amit Kumar Sinha
- Systemic Physiological and Ecotoxicological Research, Department of Biology, University of Antwerp, Antwerp, Belgium.
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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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Skowrońska M, Albrecht J. Oxidative and nitrosative stress in ammonia neurotoxicity. Neurochem Int 2012; 62:731-7. [PMID: 23142151 DOI: 10.1016/j.neuint.2012.10.013] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 10/18/2012] [Accepted: 10/28/2012] [Indexed: 12/16/2022]
Abstract
Increased ammonia accumulation in the brain due to liver dysfunction is a major contributor to the pathogenesis of hepatic encephalopathy (HE). Fatal outcome of rapidly progressing (acute) HE is mainly related to cytotoxic brain edema associated with astrocytic swelling. An increase of brain ammonia in experimental animals or treatment of cultured astrocytes with ammonia generates reactive oxygen and nitrogen species in the target tissues, leading to oxidative/nitrosative stress (ONS). In cultured astrocytes, ammonia-induced ONS is invariably associated with the increase of the astrocytic cell volume. Interrelated mechanisms underlying this response include increased nitric oxide (NO) synthesis which is partly coupled to the activation of NMDA receptors and increased generation of reactive oxygen species by NADPH oxidase. ONS and astrocytic swelling are further augmented by excessive synthesis of glutamine (Gln) which impairs mitochondrial function following its accumulation in there and degradation back to ammonia ("the Trojan horse" hypothesis). Ammonia also induces ONS in other cell types of the CNS: neurons, microglia and the brain capillary endothelial cells (BCEC). ONS in microglia contributes to the central inflammatory response, while its metabolic and pathophysiological consequences in the BCEC evolve to the vasogenic brain edema associated with HE. Ammonia-induced ONS results in the oxidation of mRNA and nitration/nitrosylation of proteins which impact intracellular metabolism and potentiate the neurotoxic effects. Simultaneously, ammonia facilitates the antioxidant response of the brain, by activating astrocytic transport and export of glutathione, in this way increasing the availability of precursors of neuronal glutathione synthesis.
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Affiliation(s)
- Marta Skowrońska
- Department of Neurotoxicology, Mossakowski Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
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McKenna MC. Substrate competition studies demonstrate oxidative metabolism of glucose, glutamate, glutamine, lactate and 3-hydroxybutyrate in cortical astrocytes from rat brain. Neurochem Res 2012; 37:2613-26. [PMID: 23079895 DOI: 10.1007/s11064-012-0901-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 10/01/2012] [Accepted: 10/03/2012] [Indexed: 01/14/2023]
Abstract
It is well established that astrocytes can utilize many substrates to support oxidative energy metabolism; however, use of energy substrates in the presence of other substrates, as would occur in vivo, has not been systematically evaluated. Substrate competition studies were used to determine changes in the rates of (14)CO(2) production since little is known about the interaction of energy substrates in astrocytes. The rates of (14)CO(2) production from 1 mM D-[6-(14)C]glucose, L-[U-(14)C]glutamate, L-[U-(14)C]glutamine, D-3-hydroxy[3-(14)C]butyrate, L-[U-(14)C]lactate and L-[U-(14)C]malate by primary cultures of astrocytes from rat brain were determined to be 1.17 ± 0.19, 85.30 ± 12.25, 28.04 ± 2.84, 13.55 ± 4.56, 14.84 ± 2.40 and 5.20 ± 1.20 nmol/h/mg protein (mean ± SEM), respectively. The rate of (14)CO(2) production from glutamate oxidation was higher than that of the other substrates Addition of unlabeled glutamate significantly decreased the rates of (14)CO(2) production from all other substrates studied; however, glutamate oxidation was not altered by the addition of any of the other substrates. The rate of (14)CO(2) production of glutamine was decreased by glutamate, but not altered by other substrates. The rate of (14)CO(2) production from glucose was significantly decreased by the addition of unlabeled glutamate, glutamine or lactate, but not by 3-hydroxybutyrate or malate. Addition of unlabeled glucose did not significantly alter the (14)CO(2) production from any other substrate. (14)CO(2) production from lactate was decreased by the addition of unlabeled glutamine or glutamate and increased by addition of malate. The (14)CO(2) production from malate was decreased by the addition of unlabeled glutamate or lactate, but was not altered by the other substrates. The substrate utilization for oxidative energy metabolism in astrocytes is very different than the profile previously reported for synaptic terminals. These studies demonstrate the potential use of multiple substrates including glucose, glutamate, glutamine, lactate and 3-hydroxybutyrate as energy substrates for astrocytes. The data also provide evidence of interactions of substrates and multiple compartments of TCA cycle activity in cultured astrocytes.
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Affiliation(s)
- Mary C McKenna
- Department of Pediatrics and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.
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The role of glutamine synthetase and glutamate dehydrogenase in cerebral ammonia homeostasis. Neurochem Res 2012; 37:2439-55. [PMID: 22618691 DOI: 10.1007/s11064-012-0803-4] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 04/24/2012] [Accepted: 05/07/2012] [Indexed: 02/07/2023]
Abstract
In the brain, glutamine synthetase (GS), which is located predominantly in astrocytes, is largely responsible for the removal of both blood-derived and metabolically generated ammonia. Thus, studies with [(13)N]ammonia have shown that about 25 % of blood-derived ammonia is removed in a single pass through the rat brain and that this ammonia is incorporated primarily into glutamine (amide) in astrocytes. Major pathways for cerebral ammonia generation include the glutaminase reaction and the glutamate dehydrogenase (GDH) reaction. The equilibrium position of the GDH-catalyzed reaction in vitro favors reductive amination of α-ketoglutarate at pH 7.4. Nevertheless, only a small amount of label derived from [(13)N]ammonia in rat brain is incorporated into glutamate and the α-amine of glutamine in vivo. Most likely the cerebral GDH reaction is drawn normally in the direction of glutamate oxidation (ammonia production) by rapid removal of ammonia as glutamine. Linkage of glutamate/α-ketoglutarate-utilizing aminotransferases with the GDH reaction channels excess amino acid nitrogen toward ammonia for glutamine synthesis. At high ammonia levels and/or when GS is inhibited the GDH reaction coupled with glutamate/α-ketoglutarate-linked aminotransferases may, however, promote the flow of ammonia nitrogen toward synthesis of amino acids. Preliminary evidence suggests an important role for the purine nucleotide cycle (PNC) as an additional source of ammonia in neurons (Net reaction: L-Aspartate + GTP + H(2)O → Fumarate + GDP + P(i) + NH(3)) and in the beat cycle of ependyma cilia. The link of the PNC to aminotransferases and GDH/GS and its role in cerebral nitrogen metabolism under both normal and pathological (e.g. hyperammonemic encephalopathy) conditions should be a productive area for future research.
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Larach DB, Kofke WA, Le Roux P. Potential non-hypoxic/ischemic causes of increased cerebral interstitial fluid lactate/pyruvate ratio: a review of available literature. Neurocrit Care 2012; 15:609-22. [PMID: 21336786 DOI: 10.1007/s12028-011-9517-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Microdialysis, an in vivo technique that permits collection and analysis of small molecular weight substances from the interstitial space, was developed more than 30 years ago and introduced into the clinical neurosciences in the 1990s. Today cerebral microdialysis is an established, commercially available clinical tool that is focused primarily on markers of cerebral energy metabolism (glucose, lactate, and pyruvate) and cell damage (glycerol), and neurotransmitters (glutamate). Although the brain comprises only 2% of body weight, it consumes 20% of total body energy. Consequently, the ability to monitor cerebral metabolism can provide significant insights during clinical care. Measurements of lactate, pyruvate, and glucose give information about the comparative contributions of aerobic and anaerobic metabolisms to brain energy. The lactate/pyruvate ratio reflects cytoplasmic redox state and thus provides information about tissue oxygenation. An elevated lactate pyruvate ratio (>40) frequently is interpreted as a sign of cerebral hypoxia or ischemia. However, several other factors may contribute to an elevated LPR. This article reviews potential non-hypoxic/ischemic causes of an increased LPR.
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Affiliation(s)
- Daniel B Larach
- University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
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Shawcross DL, Wendon JA. The neurological manifestations of acute liver failure. Neurochem Int 2011; 60:662-71. [PMID: 22067133 DOI: 10.1016/j.neuint.2011.10.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 10/12/2011] [Accepted: 10/14/2011] [Indexed: 12/12/2022]
Abstract
Acute liver failure is a disorder which impacts on multiple organ systems and results from hepatocellular necrosis in a patient with no previous history of chronic liver disease. It typically culminates in the development of liver dysfunction, coagulopathy and encephalopathy, and is associated with high mortality in poor prognostic groups. In acute liver failure, some patients may develop cerebral edema and increased intracranial pressure although recent data suggest that intracranial hypertension is less frequent than previously described, complicating 29% of acute cases who have proceeded to grade 3/4 coma. Neurological manifestations are primarily underpinned by the development of brain edema. The onset of encephalopathy can be rapid and dramatic with the development of asterixis, delirium, hyperreflexia, clonus, seizures, extensor posturing and coma. Ammonia plays a definitive role in the development of cytotoxic brain edema. Patients with acute liver failure have a marked propensity to develop renal insufficiency and hence impaired ammonia excretion. The incidence of both bacterial and fungal infection occurs in approximately one third of patients. The relationship between inflammation, as opposed to infection, and progression of encephalopathy is similar to that observed in chronic liver disease. Intracranial pressure monitoring is valuable in identifying surges in intracranial hypertension requiring intervention. Insertion of an intracranial bolt should be considered only in the subgroup of patients who have progressed to grade 4 coma. Risk factors for developing intracranial hypertension are those with hyperacute and acute etiologies, progression to grade 3/4 hepatic encephalopathy, those who develop pupillary abnormalities (dilated pupils, sluggishly responsive to light) or seizures, have systemic inflammation, an arterial ammonia >150 μmol/L, hyponatremia, and those in receipt of vasopressor support. Strategies employed in patients with established encephalopathy (grade 3/4) aim to maintain freedom from infection/inflammatory milieu, provide adequate sedation, and correct hypo-osmolality.
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Affiliation(s)
- Debbie L Shawcross
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
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Rama Rao KV, Norenberg MD. Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy. Neurochem Int 2011; 60:697-706. [PMID: 21989389 DOI: 10.1016/j.neuint.2011.09.007] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 09/16/2011] [Accepted: 09/20/2011] [Indexed: 12/22/2022]
Abstract
One proposed mechanism for acute and chronic hepatic encephalopathy (HE) is a disturbance in cerebral energy metabolism. It also reviews the current status of this mechanism in both acute and chronic HE, as well as in other hyperammonemic disorders. It also reviews abnormalities in glycolysis, lactate metabolism, citric acid cycle, and oxidative phosphorylation as well as associated energy impairment. Additionally, the role of mitochondrial permeability transition (mPT), a recently established factor in the pathogenesis of HE and hyperammonemia, is emphasized. Energy failure appears to be an important pathogenetic component of both acute and chronic HE and a potential target for therapy.
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Affiliation(s)
- Kakulavarapu V Rama Rao
- Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33125, United States
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