Abnormal brain oxygen homeostasis in an animal model of liver disease
Background & Aims: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal fun...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555922000817 |
| _version_ | 1828401081299763200 |
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| author | Anna Hadjihambi Cristina Cudalbu Katarzyna Pierzchala Dunja Simicic Chris Donnelly Christos Konstantinou Nathan Davies Abeba Habtesion Alexander V. Gourine Rajiv Jalan Patrick S. Hosford |
| author_facet | Anna Hadjihambi Cristina Cudalbu Katarzyna Pierzchala Dunja Simicic Chris Donnelly Christos Konstantinou Nathan Davies Abeba Habtesion Alexander V. Gourine Rajiv Jalan Patrick S. Hosford |
| author_sort | Anna Hadjihambi |
| collection | DOAJ |
| description | Background & Aims: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor. Methods: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration. Results: In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals. Conclusions: These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE. Lay summary: Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore. |
| first_indexed | 2024-12-10T09:42:10Z |
| format | Article |
| id | doaj.art-61b571bae53140f4bb2037e851d603c1 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-12-10T09:42:10Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-61b571bae53140f4bb2037e851d603c12022-12-22T01:53:58ZengElsevierJHEP Reports2589-55592022-08-0148100509Abnormal brain oxygen homeostasis in an animal model of liver diseaseAnna Hadjihambi0Cristina Cudalbu1Katarzyna Pierzchala2Dunja Simicic3Chris Donnelly4Christos Konstantinou5Nathan Davies6Abeba Habtesion7Alexander V. Gourine8Rajiv Jalan9Patrick S. Hosford10UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK; Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK; The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, UK; Faculty of Life Sciences and Medicine, King’s College London, London, UK; The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, UK. Tel.: (+44) 207 255 9852.CIBM Center for Biomedical Imaging, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, SwitzerlandCIBM Center for Biomedical Imaging, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, SwitzerlandCIBM Center for Biomedical Imaging, Lausanne, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, SwitzerlandInstitute of Sports Science and Department of Physiology, University of Lausanne, Lausanne, SwitzerlandThe Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, UK; Faculty of Life Sciences and Medicine, King’s College London, London, UKUCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UKUCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UKCentre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UKUCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK; European Foundation for the Study of Chronic Liver FailureCentre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK; Corresponding author. Addresses: William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, London EC1M 6BQ, UKBackground & Aims: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor. Methods: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration. Results: In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals. Conclusions: These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE. Lay summary: Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.http://www.sciencedirect.com/science/article/pii/S2589555922000817OxygenOrnithine phenylacetateChronic liver diseaseHyperammonaemiaPhenylephrinehepatic encephalopathy |
| spellingShingle | Anna Hadjihambi Cristina Cudalbu Katarzyna Pierzchala Dunja Simicic Chris Donnelly Christos Konstantinou Nathan Davies Abeba Habtesion Alexander V. Gourine Rajiv Jalan Patrick S. Hosford Abnormal brain oxygen homeostasis in an animal model of liver disease JHEP Reports Oxygen Ornithine phenylacetate Chronic liver disease Hyperammonaemia Phenylephrine hepatic encephalopathy |
| title | Abnormal brain oxygen homeostasis in an animal model of liver disease |
| title_full | Abnormal brain oxygen homeostasis in an animal model of liver disease |
| title_fullStr | Abnormal brain oxygen homeostasis in an animal model of liver disease |
| title_full_unstemmed | Abnormal brain oxygen homeostasis in an animal model of liver disease |
| title_short | Abnormal brain oxygen homeostasis in an animal model of liver disease |
| title_sort | abnormal brain oxygen homeostasis in an animal model of liver disease |
| topic | Oxygen Ornithine phenylacetate Chronic liver disease Hyperammonaemia Phenylephrine hepatic encephalopathy |
| url | http://www.sciencedirect.com/science/article/pii/S2589555922000817 |
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