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Impaired brain glymphatic flow in experimental hepatic encephalopathy.

Authors
  • Hadjihambi, Anna1
  • Harrison, Ian F2
  • Costas-Rodríguez, Marta3
  • Vanhaecke, Frank3
  • Arias, Natalia4
  • Gallego-Durán, Rocío5
  • Mastitskaya, Svetlana6
  • Hosford, Patrick S6
  • Olde Damink, Steven W M7
  • Davies, Nathan4
  • Habtesion, Abeba4
  • Lythgoe, Mark F2
  • Gourine, Alexander V6
  • Jalan, Rajiv8
  • 1 Liver Failure Group Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, NW3 2PF London, UK; Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT London, UK.
  • 2 UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, WC1E 6BT London, UK.
  • 3 Ghent University, Department of Chemistry, Atomic and Mass Spectrometry - A&MS Research Unit, Campus Sterre, Krijgslaan 281-S12, BE-9000 Ghent, Belgium. , (Belgium)
  • 4 Liver Failure Group Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, NW3 2PF London, UK.
  • 5 Institute of Biomedicine of Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, UCM Digestive Diseases & CIBERehd Sevilla, Spain. , (Spain)
  • 6 Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT London, UK.
  • 7 Department of Surgery, Maastricht University, Maastricht, the Netherlands. , (Netherlands)
  • 8 Liver Failure Group Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, NW3 2PF London, UK. Electronic address: [email protected]
Type
Published Article
Journal
Journal of hepatology
Publication Date
Jan 01, 2019
Volume
70
Issue
1
Pages
40–49
Identifiers
DOI: 10.1016/j.jhep.2018.08.021
PMID: 30201461
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Neuronal function is exquisitely sensitive to alterations in the extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain is thought to result from liver disease and may contribute to neuronal dysfunction and cognitive impairment. This study was designed to test the hypothesis that the accumulation of these substances, such as bile acids, may result from reduced clearance from the brain. In a rat model of chronic liver disease with minimal HE (the bile duct ligation [BDL] model), we used emerging dynamic contrast-enhanced MRI and mass-spectroscopy techniques to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from the brain. Immunofluorescence of aquaporin-4 (AQP4) and behavioural experiments were also performed. We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic clearance in BDL rats, which aligned with cognitive/behavioural deficits. Reduced AQP4 expression was observed in the olfactory bulb and prefrontal cortex in HE, which could contribute to the pathophysiological mechanisms underlying the impairment in glymphatic function in BDL rats. This study provides the first experimental evidence of impaired glymphatic flow in HE, potentially mediated by decreased AQP4 expression in the affected regions. The 'glymphatic system' is a newly discovered brain-wide pathway that facilitates clearance of various substances that accumulate in the brain due to its activity. This study evaluated whether the function of this system is altered in a model of brain dysfunction that occurs in cirrhosis. For the first time, we identified that the clearance of substances from the brain in cirrhosis is reduced because this clearance system is defective. This study proposes a new mechanism of brain dysfunction in patients with cirrhosis and provides new targets for therapy. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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