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Impaired brain glymphatic flow in experimental hepatic encephalopathy

Hadjihambi, A; Harrison, IF; Costas-Rodríguez, M; Vanhaecke, F; Arias, N; Gallego-Durán, R; Mastitskaya, S; ... Jalan, R; + view all (2019) Impaired brain glymphatic flow in experimental hepatic encephalopathy. Journal of Hepatology , 70 (1) pp. 40-49. 10.1016/j.jhep.2018.08.021. Green open access

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Abstract

BACKGROUND AND AIMS: Neuronal function is exquisitely sensitive to alterations in 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 be a consequence of the 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. METHODS: 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. RESULTS: We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic clearance in BDL rats, which aligned with cognitive/behavioural deficits. A significantly lower level of AQP4 expression was observed compared to the vasculature marker in both the olfactory bulb and prefrontal cortex in HE, which could be a contributing factor to the pathophysiological mechanisms underlying the impairment in glymphatic function observed in BDL rats. CONCLUSIONS: This study provides the first experimental evidence of impaired glymphatic flow in HE, potentially mediated by decreased AQP4 expression in the affected regions. LAY SUMMARY: 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.

Type: Article
Title: Impaired brain glymphatic flow in experimental hepatic encephalopathy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jhep.2018.08.021
Publisher version: https://doi.org/10.1016/j.jhep.2018.08.021
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: MRI, cirrhosis, glymphatic system, hepatic encephalopathy, mass spectrometry
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Education
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Imaging
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: https://discovery.ucl.ac.uk/id/eprint/10056649
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