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Choi K, Cho Y, Chae Y, Cheon SY. Cell-cell communications in the brain of hepatic encephalopathy: The neurovascular unit. Life Sci 2025; 363:123413. [PMID: 39863020 DOI: 10.1016/j.lfs.2025.123413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 01/07/2025] [Accepted: 01/21/2025] [Indexed: 01/27/2025]
Abstract
Many patients with liver diseases are exposed to the risk of hepatic encephalopathy (HE). The incidence of HE in liver patients is high, showing various symptoms ranging from mild symptoms to coma. Liver transplantation is one of the ways to overcome HE. However, not all patients can receive liver transplantation. Moreover, patients who have received liver transplantation have limitations in that they are vulnerable to hepatocellular carcinoma, allograft rejection, and infection. To find other therapeutic strategies, it is important to understand pathological factors and mechanisms that lead to HE after liver disease. Oxidative stress, inflammatory response, hyperammonaemia and metabolic disorders seen after liver diseases have been reported as risk factors of HE. These are known to affect the brain and cause HE. These peripheral pathological factors can impair the blood-brain barrier, cause it to collapse and damage the neurovascular unit component of multiple cells, including vascular endothelial cells, astrocytes, microglia, and neurons, leading to HE. Many previous studies on HE have suggested the impairment of neurovascular unit and cell-cell communication in the pathogenesis of HE. This review focuses on pathological factors that appear in HE, cell type-specific pathological mechanisms, miscommunication/incorrect relationships, and therapeutic candidates between brain cells in HE. This review suggests that regulating communications and interactions between cells may be important in overcoming HE.
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Affiliation(s)
- Kyuwan Choi
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Yena Cho
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Yerin Chae
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - So Yeong Cheon
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea; Research Institute for Biomedical & Health Science (RIBHS), Konkuk University, Chungju, Republic of Korea.
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Pooniya V, Chandra A, Rao S N, Singh AK, Malhotra KP. Association of Acute Kidney Injury with Ammonia Poisoning: A Case Report. Indian J Nephrol 2024; 34:395-397. [PMID: 39156836 PMCID: PMC11326797 DOI: 10.25259/ijn_9_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 07/08/2022] [Indexed: 08/20/2024] Open
Abstract
Ammonia may cause poisoning due to inhalation or ingestion. Renal involvement in ammonia poisoning has been reported only once. A 30-year-old male working in an ice factory was accidentally exposed to liquid ammonia from a leaking hose, following which he had burns over his face and neck and severe abdominal pain. On day 2, he had deranged renal function, which was progressive. He was referred to us due to persistent renal dysfunction. A kidney biopsy was performed due to slow recovery of renal failure, which was suggestive of acute tubular necrosis. He was managed conservatively and showed gradual improvement over 12 days of his hospital stay. Renal functions normalized after 14 days of discharge. This case highlights the occurrence of renal involvement in ammonia poisoning.
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Affiliation(s)
- Vishal Pooniya
- Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh, India
| | - Abhilash Chandra
- Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh, India
| | - Namrata Rao S
- Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh, India
| | - Amit K. Singh
- Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh, India
| | - Kiran P. Malhotra
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Gomti Nagar, Lucknow, Uttar Pradesh, India
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Sepehrinezhad A, Stolze Larsen F, Ashayeri Ahmadabad R, Shahbazi A, Sahab Negah S. The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review. Cells 2023; 12:cells12070979. [PMID: 37048052 PMCID: PMC10093707 DOI: 10.3390/cells12070979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, 999017 Copenhagen, Denmark
| | | | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1449614535, Iran
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Abdelghffar EAR, El-Nashar HAS, Fayez S, Obaid WA, Eldahshan OA. Ameliorative effect of oregano (Origanum vulgare) versus silymarin in experimentally induced hepatic encephalopathy. Sci Rep 2022; 12:17854. [PMID: 36284120 PMCID: PMC9596437 DOI: 10.1038/s41598-022-20412-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 09/13/2022] [Indexed: 01/20/2023] Open
Abstract
Hepatic encephalopathy (HE) is a deterioration of brain function in patients suffering from chronic liver disease, cirrhosis as a result of elevated blood ammonia and the production of pseudo-neurotransmitters. Herein, we investigated the chemical composition of hexane extract from Origanum vulgare (O. vulgare) leaves as well as its possible protective effects against thioacetamide (TAA)-induced HE in rats. GC-MS analysis of the extract revealed tentative identification of twenty-five compounds (82.93%), predominated by cholesten-3-one (27.30%), followed by γ-tocopherol (13.52%), α-tocopherol (5.01%), β-amyrin (5.24%) and α-amyrin (4.89%). Albino rats were distributed into seven groups (n = 7). G1 served as negative control; G2 and G3 served as controls treated with O. vulgare (100 and 200 mg/kg/p.o b.w, respectively); G4 served as TAA-positive control group (100 mg/kg/day/i.p., three alternative days per week for six weeks); G5, G6, and G7 served as TAA -induced HE rat model that received O. vulgare 100, O. vulgare 200, and silymarin (100 mg/kg of SILY, as standard drug), respectively. TAA showed depressive and anxiety-like behaviors in forced swimming test (FST) and reduction of cognitive score in elevated plus-maze test (EPMT) as well as impairment of locomotor and exploratory activities in open-field test (OFT). TAA caused a significant decline in body weight gain; however, the relative liver weight and brain water content were statistically increased. TAA-intoxicated rats showed significant increase of serum biomarker enzymes, proinflammatory cytokines, blood ammonia levels, brain serotonin, acetyl cholinesterase and cellular lipid peroxidation with significant decrease of brain dopamine, norepinephrine, antioxidant status. The hepatoprotective/neuro-protective activities of O. vulgare was found to be comparable with that of SILY in HE rats model. Where, treatment of TAA-intoxicated rats with O. vulgare attenuated anxiety, depressive-related behaviors, and reduced the biochemical changes in HE-induced by TAA. Therefore, O. vulgare could be an excellent hepato-/neuroprotective against hepatic injury and HE via improving the oxidative/inflammatory status through its antioxidant and neuro-modulatory properties and its effect is equal to that of SILY.
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Affiliation(s)
- Eman A. R. Abdelghffar
- grid.7269.a0000 0004 0621 1570Department of Zoology, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Heba A. S. El-Nashar
- grid.7269.a0000 0004 0621 1570Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt ,grid.7269.a0000 0004 0621 1570Centre of Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt
| | - Shaimaa Fayez
- grid.7269.a0000 0004 0621 1570Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt ,grid.7269.a0000 0004 0621 1570Centre of Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt
| | - Wael A. Obaid
- grid.412892.40000 0004 1754 9358Department of Biology, College of Science, Taibah University, Al-Madīnah Al-Munawarah, Saudi Arabia
| | - Omayma A. Eldahshan
- grid.7269.a0000 0004 0621 1570Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt ,grid.7269.a0000 0004 0621 1570Centre of Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt
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Oliveira MM, Monnet-Aimard A, Bosoi CR, Tremblay M, Rose CF. Sex is associated with differences in oxidative stress and susceptibility to severe hepatic encephalopathy in bile-duct ligated rats. J Neurochem 2022; 162:337-351. [PMID: 35771118 DOI: 10.1111/jnc.15661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/23/2022] [Accepted: 06/26/2022] [Indexed: 11/29/2022]
Abstract
Hepatic encephalopathy (HE) is a debilitating neurological complication of chronic liver disease (CLD). Hyperammonemia plays an important role in HE's pathogenesis, acting synergistically with systemic oxidative stress. During CLD, muscle plays a compensatory role in detoxifying ammonia, and therefore muscle loss leads to an increase in the risk of developing HE. With most animal studies involving males, sex's impact on the development of CLD and associated complications such as HE and muscle loss remains unknown. Therefore, we aimed to identify the impact of sex on CLD, HE, and muscle mass loss in a rodent model of CLD. Liver injury markers, hyperammonemia, oxidative stress, muscle mass and ammonia clearance were measured in female and male bile-duct ligated (BDL) rats. In addition, covert HE was assessed in females while ammonia-precipitated severe HE was assessed in female and male BDL rats, and male BDL rats treated with allopurinol (100mg/kg), an antioxidant (xanthine oxidase inhibitor). Female BDL developed CLD and HE (impaired motor-coordination and night activity) compared to respective SHAM. Hyperammonemia and muscle ammonia clearance were similar between female and male BDL. However, only female BDL rats did not develop muscle loss, brain edema, and short-term memory impairment (vs. female SHAM) and systemic oxidative stress and decreased albumin levels (vs. male BDL). Furthermore, both female BDL and allopurinol-treated male BDL rats were protected against ammonia-induced overt HE. In conclusion, female and male BDL rats develop distinct features of CLD and HE, with systemic oxidative stress playing a pivotal role in the susceptibility to ammonia precipitated overt HE.
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Affiliation(s)
- Mariana M Oliveira
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Alexis Monnet-Aimard
- Institut de Neurosciences de la Timone, Équipe inVibe, Université Aix-Marseille, France
| | - Cristina R Bosoi
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
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El Khiat A, El Hiba O, Tamegart L, Rais H, Fdil N, Sellami S, El Mokhtar MA, Gamrani H. Time dependent alteration of locomotor behavior in rat with acute liver failure induced cerebellar neuroinflammation and neuro-astroglial damage. J Chem Neuroanat 2021; 119:102055. [PMID: 34863855 DOI: 10.1016/j.jchemneu.2021.102055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/27/2021] [Accepted: 11/27/2021] [Indexed: 11/26/2022]
Abstract
Hepatic encephalopathy (HE) is a neurophysiological syndrome secondary to acute or chronic liver failure. Studies showed that HE patients exhibit a deficit in motor coordination, which may result from cerebellar functional impairment. The aim of this study is to assess the time-dependent alteration of locomotor behavior and the glial and neuronal alteration in rat with acute HE induced chemically. The study was carried out in male Sprague-Dawley rats with thioacetamide (TAA) induced acute liver failure at different stages 12 h, 24 h and 36 h. Hepatic and renal functions were assessed via various biochemical and histopathological examinations, while the cerebellum and the midbrain were examined using histology and immunohistochemistry for tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP). We used as well, the open field test and the Rotarod test for assessing the locomotor activity and coordination. Our data showed a progressive loss of liver function and a progressive alteration in locomotor behavior and motor coordination in acute HE rats. In the cerebellum, we noted an increase in the degeneration of cerebellar Purkinje neurons parallel to increased COX-2 immunoreactivity together with astrocytic morphology and density changes. Likewise, in substantia nigra pars compacta, TH levels were reduced. We showed through the current study, a progressive deterioration in locomotor behavior in acute HE rats, as a result of Purkinje neurons death and a deficient dopaminergic neurotransmission, together with the morpho-functional astroglial modifications involving the oxidative stress and neuroinflammation.
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Affiliation(s)
- Abdelaati El Khiat
- Laboratory of Clinical and Experimental Neurosciences and Environment, faculty of Medicine and Pharmacy, Cadi Ayyad University, 4000 Marrakech, Morocco; Higher Institute of Nursing Professions and Health Techniques, Ouarzazate, Morocco.
| | - Omar El Hiba
- Nutritional Physiopathologies and Toxicology Team, faculty of Sciences, Chouaib Doukkali University, El Jadida, Morocco.
| | - Lahcen Tamegart
- Laboratory of Clinical and Experimental Neurosciences and Environment, faculty of Medicine and Pharmacy, Cadi Ayyad University, 4000 Marrakech, Morocco; Department of Biology, Faculty of Science, Abdelmalek Essaadi University, Tetouan, Morocco
| | - Hanane Rais
- Laboratory of Morphosciences, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Morocco; Mohammed VI University Hospital, Marrakech, Morocco
| | - Naima Fdil
- Metabolics platform, Biochemistry Laboratory, Faculty of Medicine, Cadi Ayyad University, Sidi Abbad, BP 40000 Marrakech, Morocco
| | | | - Mohamed Ait El Mokhtar
- Laboratory of Biochemistry, Environment &Agri-food URAC 36, Department of Biology, Faculty of Sciences and Techniques, Mohmmedia, Hassan II University of Casablanca, Morocco
| | - Halima Gamrani
- Laboratory of Clinical and Experimental Neurosciences and Environment, faculty of Medicine and Pharmacy, Cadi Ayyad University, 4000 Marrakech, Morocco.
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DeMorrow S, Cudalbu C, Davies N, Jayakumar AR, Rose CF. 2021 ISHEN guidelines on animal models of hepatic encephalopathy. Liver Int 2021; 41:1474-1488. [PMID: 33900013 PMCID: PMC9812338 DOI: 10.1111/liv.14911] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/05/2021] [Accepted: 04/01/2021] [Indexed: 02/07/2023]
Abstract
This working group of the International Society of Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) was commissioned to summarize and update current efforts in the development and characterization of animal models of hepatic encephalopathy (HE). As defined in humans, HE in animal models is based on the underlying degree and severity of liver pathology. Although hyperammonemia remains the key focus in the pathogenesis of HE, other factors associated with HE have been identified, together with recommended animal models, to help explore the pathogenesis and pathophysiological mechanisms of HE. While numerous methods to induce liver failure and disease exist, less have been characterized with neurological and neurobehavioural impairments. Moreover, there still remains a paucity of adequate animal models of Type C HE induced by alcohol, viruses and non-alcoholic fatty liver disease; the most common etiologies of chronic liver disease.
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Affiliation(s)
- S DeMorrow
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Texas, USA; Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Texas, USA; Research division, Central Texas Veterans Healthcare System, Temple Texas USA.,Correspondance: Sharon DeMorrow, PhD, ; tel: +1-512-495-5779
| | - C Cudalbu
- Center for Biomedical Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - N Davies
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - AR Jayakumar
- General Medical Research, Neuropathology Section, R&D Service and South Florida VA Foundation for Research and Education Inc; Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami FL, USA
| | - CF Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
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Management of Hepatic Encephalopathy in the Neurocritical Care Unit. Neurocrit Care 2019. [DOI: 10.1017/9781107587908.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Cudalbu C, Taylor-Robinson SD. Brain Edema in Chronic Hepatic Encephalopathy. J Clin Exp Hepatol 2019; 9:362-382. [PMID: 31360029 PMCID: PMC6637228 DOI: 10.1016/j.jceh.2019.02.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 01/15/2019] [Accepted: 02/06/2019] [Indexed: 02/07/2023] Open
Abstract
Brain edema is a common feature associated with hepatic encephalopathy (HE). In patients with acute HE, brain edema has been shown to play a crucial role in the associated neurological deterioration. In chronic HE, advanced magnetic resonance imaging (MRI) techniques have demonstrated that low-grade brain edema appears also to be an important pathological feature. This review explores the different methods used to measure brain edema ex vivo and in vivo in animal models and in humans with chronic HE. In addition, an in-depth description of the main studies performed to date is provided. The role of brain edema in the neurological alterations linked to HE and whether HE and brain edema are the manifestations of the same pathophysiological mechanism or two different cerebral manifestations of brain dysfunction in liver disease are still under debate. In vivo MRI/magnetic resonance spectroscopy studies have allowed insight into the development of brain edema in chronic HE. However, additional in vivo longitudinal and multiparametric/multimodal studies are required (in humans and animal models) to elucidate the relationship between liver function, brain metabolic changes, cellular changes, cell swelling, and neurological manifestations in chronic HE.
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Key Words
- 1H MRS, proton magnetic resonance spectroscopy
- ADC, apparent diffusion coefficient
- ALF, acute liver failure
- AQP, aquaporins
- BBB, blood-brain barrier
- BDL, bile duct ligation
- CNS, central nervous system
- CSF, cerebrospinal fluid
- Cr, creatine
- DTI, diffusion tensor imaging
- DWI, diffusion-weighted imaging
- FLAIR, fluid-attenuated inversion recovery
- GM, gray matter
- Gln, glutamine
- Glx, sum of glutamine and glutamate
- HE, hepatic encephalopathy
- Ins, inositol
- LPS, lipopolysaccharide
- Lac, lactate
- MD, mean diffusivity
- MRI, magnetic resonance imaging
- MRS, magnetic resonance spectroscopy
- MT, magnetization transfer
- MTR, MT ratio
- NMR, nuclear magnetic resonance
- PCA, portocaval anastomosis
- TE, echo time
- WM, white matter
- brain edema
- chronic hepatic encephalopathy
- in vivo magnetic resonance imaging
- in vivo magnetic resonance spectroscopy
- liver cirrhosis
- mIns, myo-inositol
- tCho, total choline
- tCr, total creatine
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Affiliation(s)
- Cristina Cudalbu
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Simon D. Taylor-Robinson
- Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, St Mary's Hospital Campus, Imperial College London, London, United Kingdom
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Bashiri H, Hosseini-Chegeni H, Alsadat Sharifi K, Sahebgharani M, Salari AA. Activation of TRPV1 receptors affects memory function and hippocampal TRPV1 and CREB mRNA expression in a rat model of biliary cirrhosis. Neurol Res 2018; 40:938-947. [PMID: 30079821 DOI: 10.1080/01616412.2018.1504158] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Memory impairment induced by biliary cirrhosis is associated with abnormalities in the function of different neurotransmitter systems. However, the exact molecular mechanisms involved in the learning and memory dysfunctions following biliary cirrhosis is largely unknown. This study set out to determine whether activation of transient receptor potential vanilloid type 1 (TRPV1) in the CA1 area of the hippocampus in rats improve memory impairment induced by biliary cirrhosis. METHODS To assess learning and memory, passive avoidance task was carried out using a shuttle box. The mRNA expression of TRPV1 and cAMP response element binding (CREB) protein in the hippocampus were also evaluated by qT-PCR. RESULTS Our results indicated that activation of TRPV1 channels by capsaicin significantly decreased memory impairment and increased mRNA expression of the TRPV1 and CREB in the hippocampus of rats with biliary cirrhosis. Our findings also demonstrated that a positive correlation existed between mRNA expression of TRPV1 and CREB, and between memory function and TRPV1 expression. DISCUSSION Taken together, the results of this study support the view that TRPV1 receptor may play an important role in the regulation of learning and memory functions, and suggest that activation of TRPV1 channels seems to be a promising therapeutic target for learning and memory impairments following biliary cirrhosis.
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Affiliation(s)
- Hamideh Bashiri
- a Neuroscience Research Center, Institute of Neuropharmacology , Department of Physiology and Pharmacology, Afzalipour School of Medical, Kerman University of Medical Sciences , Kerman , Iran
| | | | - Khadijeh Alsadat Sharifi
- c Department of Neuroscience , School of Advanced Technologies in Medicine, Tehran University of Medical Sciences , Tehran , Iran
| | - Mousa Sahebgharani
- d Department of Pharmacology , School of Medicine, Tehran University of Medical Sciences , Tehran , Iran
| | - Ali-Akbar Salari
- e Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran
- f Salari Institute of Cognitive and Behavioral Disorders (SICBD) , Alborz , Iran
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Mendes NF, Mariotti FFN, de Andrade JS, de Barros Viana M, Céspedes IC, Nagaoka MR, Le Sueur-Maluf L. Lactulose decreases neuronal activation and attenuates motor behavioral deficits in hyperammonemic rats. Metab Brain Dis 2017; 32:2073-2083. [PMID: 28875419 DOI: 10.1007/s11011-017-0098-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 08/16/2017] [Indexed: 12/14/2022]
Abstract
Lactulose is a nonabsorbable disaccharide commonly used in clinical practice to treat hepatic encephalopathy. However, its effects on neuropsychiatric disorders and motor behavior have not been fully elucidated. Male Wistar rats were bile-duct ligated, and 3 weeks after surgery, treated with lactulose administrated by gavage (1.43 or 3.57 g/kg), once a day for seven days. Plasma levels of ammonia, aspartate aminotransferase, total bilirubin, and creatinine were quantified and histopathological analysis of the livers was performed. Locomotor activity measurements were performed in an open field. The expression of water channel aquaporin-4 was investigated and the analysis of Fos protein immunoreactivity was used to evaluate the pattern of neural activation in brain areas related to motor behavior. Bile-duct ligated rats showed hyperammonemia, loss of liver integrity and function, impaired locomotor activity, reduced aquaporin-4 protein expression, and neuronal hyperactivity. Lactulose treatment was able to reduce ammonia plasma levels, despite not having an effect on biochemical parameters of liver function, such as aspartate aminotransferase activity and total bilirubin levels, or on the cirrhotic hepatic architecture. Lactulose was also able to reduce the locomotor activity impairments and to mitigate or reverse most changes in neuronal activation. Lactulose had no effect on reduced aquaporin-4 protein expression. Our findings confirm the effectiveness of lactulose in reducing hyperammonemia and neuronal hyperactivity in brain areas related to motor behavior, reinforcing the importance of its clinical use in the treatment of the symptoms of cirrhosis-associated encephalopathy.
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Affiliation(s)
- Natália Ferreira Mendes
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
- Laboratório de Sinalização Celular, Universidade Estadual de Campinas, UNICAMP, Campinas/SP, 13083-864, Brazil
| | - Flora França Nogueira Mariotti
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
| | - José Simões de Andrade
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
| | - Milena de Barros Viana
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
| | - Isabel Cristina Céspedes
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
- Departamento de Morfologia e Genética, Universidade Federal de São Paulo, UNIFESP, 11015-020, São Paulo/SP, 04023-900, Brazil
| | - Márcia Regina Nagaoka
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
| | - Luciana Le Sueur-Maluf
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil.
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Jamshidzadeh A, Heidari R, Latifpour Z, Ommati MM, Abdoli N, Mousavi S, Azarpira N, Zarei A, Zarei M, Asadi B, Abasvali M, Yeganeh Y, Jafari F, Saeedi A, Najibi A, Mardani E. Carnosine ameliorates liver fibrosis and hyperammonemia in cirrhotic rats. Clin Res Hepatol Gastroenterol 2017; 41:424-434. [PMID: 28283328 DOI: 10.1016/j.clinre.2016.12.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/24/2016] [Accepted: 12/28/2016] [Indexed: 02/04/2023]
Abstract
AIM Chronic liver injury and cirrhosis leads to liver failure. Hyperammonemia is a deleterious consequence of liver failure. On the other hand, oxidative stress seems to play a pivotal role in the pathogenesis of liver fibrosis as well as in the cytotoxic mechanism of ammonia. There is no promising therapeutic agent against ammonia-induced complications. The present study was conducted to evaluate the role of carnosine (CA) administration on liver pathological changes, elevated plasma ammonia, and its consequent events in cirrhotic rats. METHODS Bile duct ligated (BDL) rats were used as a model of cirrhosis. CA (250, 500, and 1000mg/kg, daily, i.p) was administered for 28 consecutive days to BDL animals. At the end of treatments, markers of oxidative stress and liver fibrosis was determined in liver and serum biomarkers of liver injury and plasma ammonia was assessed. Moreover, changes in animals' locomotor activity were monitored. RESULTS Severe bridging fibrosis, inflammation, and necrosis in liver, along with elevated serum biomarkers of liver injury were evident in BDL animals. Furthermore, plasma ammonia was drastically elevated in cirrhotic rats and animals' locomotor activity was suppressed. It was found that CA (250, 500, and 1000mg/kg, daily, i.p) significantly alleviated liver injury and its consequent events in cirrhotic rats. The data suggested that CA is not only a useful and safe agent to preserve liver function, but also prevented hyperammonemia and brain damage as a deleterious consequence of cirrhosis and liver failure.
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Affiliation(s)
- Akram Jamshidzadeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 1583, 71345 Roknabad, Karafarin Street, Shiraz, Fars, 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, P.O. Box 1583, 71345 Roknabad, Karafarin Street, Shiraz, Fars, Iran.
| | - Zahra Latifpour
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammed Mehdi Ommati
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 1583, 71345 Roknabad, Karafarin Street, Shiraz, Fars, Iran
| | - Narges Abdoli
- Iran Food and Drug Administration (IFDA), Ministry of Health, Tehran, Iran
| | - Somayeh Mousavi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Azita Zarei
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdi Zarei
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Behnam Asadi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mojgan Abasvali
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Yasaman Yeganeh
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Faezeh Jafari
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arastoo Saeedi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asma Najibi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elnaz Mardani
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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Carnosine protects brain mitochondria under hyperammonemic conditions: Relevance to hepatic encephalopathy treatment. PHARMANUTRITION 2017. [DOI: 10.1016/j.phanu.2017.02.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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14
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Glutamine triggers long-lasting increase in striatal network activity in vitro. Exp Neurol 2017; 290:41-52. [DOI: 10.1016/j.expneurol.2017.01.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 12/05/2016] [Accepted: 01/04/2017] [Indexed: 01/04/2023]
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15
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Li Y, Mei LH, Qiang JW, Ji CX, Ju S. Reduction of manganese intake improves neuropsychological manifestations in rats with minimal hepatic encephalopathy. Neuroscience 2017; 347:148-155. [DOI: 10.1016/j.neuroscience.2017.02.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/02/2017] [Accepted: 02/02/2017] [Indexed: 01/06/2023]
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16
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Dasarathy S, Mookerjee RP, Rackayova V, Rangroo Thrane V, Vairappan B, Ott P, Rose CF. Ammonia toxicity: from head to toe? Metab Brain Dis 2017; 32:529-538. [PMID: 28012068 PMCID: PMC8839071 DOI: 10.1007/s11011-016-9938-3] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 11/30/2016] [Indexed: 12/14/2022]
Abstract
Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction.
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Affiliation(s)
- Srinivasan Dasarathy
- Department of Gastroenterology, Hepatology and Pathobiology, Cleveland Clinic, Cleveland, OH, USA
| | - Rajeshwar P Mookerjee
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK
| | - Veronika Rackayova
- Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Vinita Rangroo Thrane
- Department of Ophthalmology, Haukeland University Hospital, 5021, Bergen, Norway
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, USA
| | - Balasubramaniyan Vairappan
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantri Nagar, Pondicherry, India
| | - Peter Ott
- Department of Medicine V (Hepatology and Gastroenterology), Aarhus, Denmark
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
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Brusilow WSA, Peters TJ. Therapeutic effects of methionine sulfoximine in multiple diseases include and extend beyond inhibition of glutamine synthetase. Expert Opin Ther Targets 2017; 21:461-469. [PMID: 28292200 DOI: 10.1080/14728222.2017.1303484] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
INTRODUCTION Methionine sulfoximine (MSO), a well-characterized inhibitor of glutamine synthetase, displays significant therapeutic benefits in animal models for several human diseases. This amino acid might therefore be a viable candidate for drug development to treat diseases for which there are few effective therapies. Areas covered: We describe the effects of MSO on brain swelling occurring in overt hepatic encephalopathy resulting from liver failure, the effects of MSO on excitotoxic damage involved in amyotrophic lateral sclerosis (ALS) or resulting from stroke, and the effects of MSO on a model for an inflammatory immune response involved in a range of diseases. We conclude that these results imply the existence of another therapeutic target for MSO in addition to glutamine synthetase. Expert opinion: We summarize the various diseases for which MSO treatment might be a candidate for drug development. We discuss why MSO has limited enthusiasm in the scientific and medical communities for use in humans, with a rebuttal to those negative opinions. And we conclude that MSO should be considered a candidate drug to treat brain swelling involved in overt hepatic encephalopathy and diseases involving an inflammatory immune response.
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Affiliation(s)
- William S A Brusilow
- a Department of Biochemistry and Molecular Biology , Wayne State University School of Medicine , Detroit , MI , USA
| | - Tyler J Peters
- a Department of Biochemistry and Molecular Biology , Wayne State University School of Medicine , Detroit , MI , USA
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18
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Affiliation(s)
- Eelco F M Wijdicks
- From the Division of Critical Care Neurology, Mayo Clinic, Rochester, MN
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19
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Oeltzschner G, Butz M, Wickrath F, Wittsack HJ, Schnitzler A. Covert hepatic encephalopathy: elevated total glutathione and absence of brain water content changes. Metab Brain Dis 2016; 31:517-27. [PMID: 26563124 DOI: 10.1007/s11011-015-9760-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 11/06/2015] [Indexed: 01/20/2023]
Abstract
Recent pathophysiological models suggest that oxidative stress and hyperammonemia lead to a mild brain oedema in hepatic encephalopathy (HE). Glutathione (GSx) is a major cellular antioxidant and known to be involved in the interception of both. The aim of this work was to study total glutathione levels in covert HE (minimal HE and HE grade 1) and to investigate their relationship with local brain water content, levels of glutamine (Gln), myo-inositol (mI), neurotransmitter levels, critical flicker frequency (CFF), and blood ammonia. Proton magnetic resonance spectroscopy ((1)H MRS) data were analysed from visual and sensorimotor cortices of thirty patients with covert HE and 16 age-matched healthy controls. Total glutathione levels (GSx/Cr) were quantified with respect to creatine. Furthermore, quantitative MRI brain water content measures were evaluated. Data were tested for links with the CFF and blood ammonia. GSx/Cr was elevated in the visual (mHE) and sensorimotor (mHE, HE 1) MRS volumes and correlated with blood ammonia levels (both P < 0.001). It was further linked to Gln/Cr and mI/Cr (P < 0.01 in visual, P < 0.001 in sensorimotor) and to GABA/Cr (P < 0.01 in visual). Visual GSx/Cr correlated with brain water content in the thalamus, nucleus caudatus, and visual cortex (P < 0.01). Brain water measures did neither show group effects nor correlations with CFF or blood ammonia. Elevated total glutathione levels in covert HE (< HE 2) correlate with blood ammonia and may be a regional-specific reaction to hyperammonemia and oxidative stress. Brain water content is locally linked to visual glutathione levels, but appears not to be associated with changes of clinical parameters. This might suggest that cerebral oedema is only marginally responsible for the symptoms of covert HE.
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Affiliation(s)
- Georg Oeltzschner
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany.
- Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, D-40225, Düsseldorf, Germany.
| | - Markus Butz
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany
| | - Frithjof Wickrath
- Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, D-40225, Düsseldorf, Germany
| | - Hans-Jörg Wittsack
- Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, D-40225, Düsseldorf, Germany
| | - Alfons Schnitzler
- Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany
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20
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Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia. Toxicol Rep 2016; 3:870-879. [PMID: 28959615 PMCID: PMC5615919 DOI: 10.1016/j.toxrep.2016.04.002] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 03/19/2016] [Accepted: 04/08/2016] [Indexed: 12/20/2022] Open
Abstract
Hyperammonemia is associated with chronic and acute liver injury. There is no promising therapeutic agent against ammonia-induced complications. Hence, finding therapeutic molecules with safe profile of administration has clinical value. The present study was conducted to evaluate the role of taurine (TA) administration on plasma and brain ammonia and its consequent events in different models of chronic and acute liver injury and hyperammonemia. Bile duct ligated (BDL) rats were used as a model of chronic liver injury. Thioacetamide and acetaminophen-induced acute liver failure were used as acute liver injury models. A high level of ammonia was detected in blood and brain of experimental groups. An increase in brain ammonia level coincided with a decreased total locomotor activity of animals and significant changes in the biochemistry of blood and also liver tissue. TA administration (500 and 1000 mg/kg, i.p), effectively alleviated liver injury and its consequent events including rise in plasma and brain ammonia and brain edema. The data suggested that TA is not only a useful and safe agent to preserve liver function, but also prevented hyperammonemia as a deleterious consequence of acute and chronic liver injury.
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21
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Milewski K, Hilgier W, Fręśko I, Polowy R, Podsiadłowska A, Zołocińska E, Grymanowska AW, Filipkowski RK, Albrecht J, Zielińska M. Carnosine Reduces Oxidative Stress and Reverses Attenuation of Righting and Postural Reflexes in Rats with Thioacetamide-Induced Liver Failure. Neurochem Res 2016; 41:376-84. [PMID: 26801175 PMCID: PMC4773466 DOI: 10.1007/s11064-015-1821-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 12/28/2015] [Accepted: 12/29/2015] [Indexed: 12/25/2022]
Abstract
Cerebral oxidative stress (OS) contributes to the pathogenesis of hepatic encephalopathy (HE). Existing evidence suggests that systemic administration of l-histidine (His) attenuates OS in brain of HE animal models, but the underlying mechanism is complex and not sufficiently understood. Here we tested the hypothesis that dipeptide carnosine (β-alanyl-l-histidine, Car) may be neuroprotective in thioacetamide (TAA)-induced liver failure in rats and that, being His metabolite, may mediate the well documented anti-OS activity of His. Amino acids [His or Car (100 mg/kg)] were administrated 2 h before TAA (i.p., 300 mg/kg 3× in 24 h intervals) injection into Sprague–Dawley rats. The animals were thus tested for: (i) brain prefrontal cortex and blood contents of Car and His, (ii) amount of reactive oxygen species (ROS), total antioxidant capacity (TAC), GSSG/GSH ratio and thioredoxin reductase (TRx) activity, and (iii) behavioral changes (several models were used, i.e. tests for reflexes, open field, grip test, Rotarod). Brain level of Car was reduced in TAA rats, and His administration significantly elevated Car levels in control and TAA rats. Car partly attenuated TAA-induced ROS production and reduced GSH/GSSG ratio, whereas the increase of TRx activity in TAA brain was not significantly modulated by Car. Further, Car improved TAA-affected behavioral functions in rats, as was shown by the tests of righting and postural reflexes. Collectively, the results support the hypothesis that (i) Car may be added to the list of neuroprotective compounds of therapeutic potential on HE and that (ii) Car mediates at least a portion of the OS-attenuating activity of His in the setting of TAA-induced liver failure.
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Affiliation(s)
- Krzysztof Milewski
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Wojciech Hilgier
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Inez Fręśko
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Rafał Polowy
- Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Anna Podsiadłowska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Ewa Zołocińska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Aneta W Grymanowska
- Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Robert K Filipkowski
- Behavior and Metabolism Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Jan Albrecht
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland.
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Mayer LB, Krawczyk M, Grünhage F, Lammert F, Stokes CS. A genetic variant in the promoter of phosphate-activated glutaminase is associated with hepatic encephalopathy. J Intern Med 2015; 278:313-22. [PMID: 25880019 DOI: 10.1111/joim.12374] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis. Recently, a microsatellite in the promoter region of the phosphate-activated glutaminase (GLS ) gene was associated with the risk of HE. The aim of the present study was to investigate, using the critical flicker frequency (CFF) test, whether the described GLS variant increases the risk of developing HE in patients with cirrhosis. METHODS We recruited 158 patients (66% men; mean age 59 years, range 23-86) with liver cirrhosis. Mean model for end-stage liver disease score was 13.8 (range 5-35); 48% of patients presented with Child-Pugh score B or C. The presence and severity of HE were determined by the CFF test, with frequencies ≤39 Hz denoting cases. GLS variants were genotyped by sequencing the microsatellite in the promoter region and were classified as short, long or short-long forms (depending on the length of the macrosatellite alleles). RESULTS In total, 53% of patients had abnormal CFF results (i.e. ≤39 Hz; range for entire cohort 26-57). The GLS microsatellite distribution amongst patients was short form (20%), long form (32%) and short-long form (48%) and was consistent with Hardy-Weinberg equilibrium. CFF values differed significantly between groups (P = 0.043). Carriers of the GLS long microsatellite had a significantly higher risk of HE according to multivariate analyses (odds ratio 3.23, 95% confidence interval 1.46-7.13, P = 0.004). CONCLUSION CFF results were significantly lower amongst carriers of the GLS long microsatellite. Our findings support the role of the GLS long microsatellite in the development of HE; this could be important for identifying susceptible patients and for the prevention of this condition.
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Affiliation(s)
- L B Mayer
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - M Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.,Laboratory of Metabolic Liver Diseases, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - F Grünhage
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - F Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - C S Stokes
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
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23
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Dilektasli E, Ozmen MM, Gundogdu E, Dizen H, Besler HT, Ozogul C. The effects of obstructive jaundice on the brain: An experimental study. Asian J Surg 2015; 39:155-63. [PMID: 26187138 DOI: 10.1016/j.asjsur.2015.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 03/18/2015] [Accepted: 03/19/2015] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND/OBJECTIVE The study aims to evaluate the alterations in the brain due to oxidative stress and lipid peroxidation resulting from obstructive jaundice. METHODS Forty-one Wistar albino rats were used in this study. Simple laparotomy was performed in the sham group (n = 5). In the remaining 36 rats, the common bile duct (CBD) was found and ligated. They were divided into six groups. Group I, Group II, and Group III were sacrificed at the 3(rd), 7(th), and 14(th) day of ligation, respectively. In Group Id, Group IId, and Group IIId ligated bile ducts were decompressed at the 3(rd), 7(th), and 14(th) day, respectively. One week after decompression these rats were also sacrificed and samples were taken. RESULTS After the CBD ligation, serum levels of bilirubin and malondialdehyde were found to be increased progressively in parallel to the ligation time of the CBD. After decompression these values decreased. In electron microscopy evaluation, the damage was found to be irreversible depending on the length of the obstruction period. In Group II, the damage was mostly reversible after the internal drainage period of 7 days. However in Group III, the tissue damage was found to be irreversible despite the decreased values of oxidative stress and bilirubin. CONCLUSION Ultrastructural changes in brain tissue including damage in the glial cells and neurons, were found to be irreversible if the CBD ligation period was >7 days and did not regress even after decompression. It is unreliable to trace these changes using blood levels of bilirubin and free radicals. Therefore, timing is extremely critical for medical therapies and drainage.
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Affiliation(s)
- Evren Dilektasli
- Acute Care Surgery and Surgical Critical Care, Department of General Surgery, Medical School, USC, Los Angeles, CA, USA; Department of General Surgery, Sevket Yilmaz Training and Research Hospital, Bursa, Turkey.
| | - M M Ozmen
- Department of General Surgery, Medical School, Hacettepe University, Ankara, Turkey
| | - Emre Gundogdu
- Department of General Surgery, Batman State Hospital, Batman, Turkey
| | - Hayrettin Dizen
- Department of General Surgery, Yunus Emre State Hospital, Eskisehir, Turkey
| | - H T Besler
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Turkey
| | - Candan Ozogul
- Department of Histology and Embryology, Medical School, Gazi University, Ankara, Turkey
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Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy. Neurochem Int 2014; 88:15-9. [PMID: 25447766 DOI: 10.1016/j.neuint.2014.10.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 10/11/2014] [Accepted: 10/29/2014] [Indexed: 12/13/2022]
Abstract
The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia-thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy.
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25
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Zhang XD, Zhang LJ, Wu SY, Lu GM. Multimodality magnetic resonance imaging in hepatic encephalopathy: An update. World J Gastroenterol 2014; 20:11262-11272. [PMID: 25170210 PMCID: PMC4145764 DOI: 10.3748/wjg.v20.i32.11262] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 01/29/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric complication of cirrhosis or acute liver failure. Currently, HE is regarded as a continuous cognitive impairment ranging from the mildest stage, minimal HE to overt HE. Hyperammonaemia and neuroinflammation are two main underlying factors which contribute to the neurological alterations in HE. Both structural and functional impairments are found in the white mater and grey mater involved in HE. Although the investigations into HE pathophysiological mechanism are enormous, the exact pathophysiological causes underlying HE remain controversial. Multimodality magnetic resonance imaging (MRI) plays an important role in helping to understand the pathological process of HE. This paper reviews the up-to-date multimodality MRI methods and predominant findings in HE patients with a highlight of the increasingly important role of blood oxygen level dependent functional MRI.
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Abstract
Liver failure affects brain function, leading to neurological and psychiatric alterations; such alterations are referred to as hepatic encephalopathy (HE). Early diagnosis of minimal HE reveals an unexpectedly high incidence of mild cognitive impairment and psychomotor slowing in patients with liver cirrhosis - conditions that have serious health, social and economic consequences. The mechanisms responsible for the neurological alterations in HE are beginning to emerge. New therapeutic strategies acting on specific targets in the brain (phosphodiesterase 5, type A GABA receptors, cyclooxygenase and mitogen-activated protein kinase p38) have been shown to restore cognitive and motor function in animal models of chronic HE, and NMDA receptor antagonists have been shown to increase survival in acute liver failure. This article reviews the latest studies aimed at understanding how liver failure affects brain function and potential ways to ameliorate these effects.
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