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Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia

Marini, S, Santangeli, O, Saarelainen, P, Middleton, Benita, Chowdhury, Namrata Roy, Skene, Debra, Costa, R, Porkka-Heiskanen, T and Montagnese, S (2017) Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia Frontiers in Physiology, 8, 636.

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Abstract

Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking EEG. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 hours of sleep deprivation. Adenosine and metabolite levels were measured by HPLC and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Marini, SUNSPECIFIEDUNSPECIFIED
Santangeli, OUNSPECIFIEDUNSPECIFIED
Saarelainen, PUNSPECIFIEDUNSPECIFIED
Middleton, BenitaB.Middleton@surrey.ac.ukUNSPECIFIED
Chowdhury, Namrata Royn.chowdhury@surrey.ac.ukUNSPECIFIED
Skene, DebraD.Skene@surrey.ac.ukUNSPECIFIED
Costa, RUNSPECIFIEDUNSPECIFIED
Porkka-Heiskanen, TUNSPECIFIEDUNSPECIFIED
Montagnese, SUNSPECIFIEDUNSPECIFIED
Date : 31 August 2017
Identification Number : 10.3389/fphys.2017.00636
Copyright Disclaimer : Copyright © 2017 Marini, Santangeli, Saarelainen, Middleton, Chowdhury, Skene, Costa, Porkka-Heiskanen and Montagnese. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Uncontrolled Keywords : Hyperammonemia, Hepatic Encephalopathy, sleep homeostasis, Adenosine, Metabolomics/Metabolite Profiling
Depositing User : Melanie Hughes
Date Deposited : 16 Aug 2017 07:48
Last Modified : 08 Sep 2017 09:02
URI: http://epubs.surrey.ac.uk/id/eprint/841937

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