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Longitudinal neurometabolic changes in the hippocampus of a rat model of chronic hepatic encephalopathy

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Braissant Olivier, Rackayová Veronika, Pierzchala Katarzyna, Grosse Jocelyn, McLin Valérie, Cudalbu Cristina,
Project Translational Non-Invasive Metabolic Studies towards Novel Treatments of Chronic Hepatic Encephalopathy in Developing Brain, from 3D Organotypic Brain Cell Cultures to the In vivo Rat and Human Brain
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Original article (peer-reviewed)

Journal Journal of Hepatology
Volume (Issue) 71(3)
Page(s) 505 - 515
Title of proceedings Journal of Hepatology
DOI 10.1016/j.jhep.2019.05.022

Open Access

Type of Open Access Publisher (Gold Open Access)


Background & aims: The sequence of events in hepatic encephalopathy (HE) remains unclear. Using the advantages of in vivo 1H-MRS (9.4T) we aimed to analyse the time-course of disease in an established model of type C HE by analysing the longitudinal changes in a large number of brain metabolites together with biochemical, histological and behavioural assessment. We hypothesized that neurometabolic changes are detectable very early, and that these early changes will offer insight into the primary events underpinning HE. Methods: Wistar rats underwent bile-duct ligation (BDL) and were studied before BDL and at post-operative weeks 2, 4, 6 and 8 (n = 26). In vivo short echo-time 1H-MRS (9.4T) of the hippocampus was performed in a longitudinal manner, as were biochemical (plasma), histological and behavioural tests. Results: Plasma ammonium increased early after BDL and remained high during the study. Brain glutamine increased (+47%) as early as 2-4 weeks post-BDL while creatine (-8%) and ascorbate (-12%) decreased. Brain glutamine and ascorbate correlated closely with rising plasma ammonium, while brain creatine correlated with brain glutamine. The increases in brain glutamine and plasma ammonium were correlated, while plasma ammonium correlated negatively with distance moved. Changes in astrocyte morphology were observed at 4 weeks. These early changes were further accentuated at 6-8 weeks post-BDL, concurrently with the known decreases in brain organic osmolytes. Conclusion: Using a multimodal, in vivo and longitudinal approach we have shown that neurometabolic changes are already noticeable 2 weeks after BDL. These early changes are suggestive of osmotic/oxidative stress and are likely the premise of some later changes. Early decreases in cerebral creatine and ascorbate are novel findings offering new avenues to explore neuroprotective strategies for HE treatment.