Abnormal brain oxygen homeostasis in an animal model of liver disease.
1H-MRS, proton magnetic resonance spectroscopy
AIT, Animal Imaging and Technology
ALT, alanine transaminase
ATZ, acetazolamide
Ala, alanine
Asc, ascorbate
Asp, aspartate
BDL, bile duct ligation
BOLD, blood oxygen level dependent
BP, blood pressure
CBF, cerebral blood flow
CIBM, Center for Biomedical Imaging
CLD, chronic liver disease
CMRO2, cerebral metabolic rate of oxygen
CNS, central nervous system
Chronic liver disease
Cr, creatine
EPFL, Ecole Polytechnique Fédérale de Lausanne
GABA, γ-aminobutyric acid
GPC, glycerophosphocholine
GSH, glutathione
Glc, glucose
Gln, glutamine
Glu, glutamate
HE, hepatic encephalopathy
Hyperammonaemia
Ins, myo-inositol
Lac, lactate
MAP, mean arterial pressure
NAA, N acetylaspartate
NO, nitric oxide
OP, ornithine phenylacetate
Ornithine phenylacetate
Oxygen
PCho, phosphocholine
PCr, phosphocreatine
PE, phenylephrine
Phenylephrine
SPECIAL, spin echo full intensity acquired localised
TE, echo time
Tau, taurine
VOI, volume of interest
[18F]-FDG PET, [18F]-fluorodeoxyglucose positron emission tomography
eNOS, endothelial nitric oxide synthase
fMRI, functional magnetic resonance imaging
hepatic encephalopathy
mHE, minimal HE
pCO2, partial pressure of carbon dioxide
pO2, partial pressure of oxygen
tCho, total choline
tCr, total creatine
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Aug 2022
Aug 2022
Historique:
received:
23
12
2021
revised:
23
04
2022
accepted:
10
05
2022
entrez:
22
7
2022
pubmed:
23
7
2022
medline:
23
7
2022
Statut:
epublish
Résumé
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. 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. 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 CO 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. 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.
Sections du résumé
Background & Aims
UNASSIGNED
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
UNASSIGNED
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
UNASSIGNED
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 CO
Conclusions
UNASSIGNED
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
UNASSIGNED
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.
Identifiants
pubmed: 35865351
doi: 10.1016/j.jhepr.2022.100509
pii: S2589-5559(22)00081-7
pmc: PMC9293761
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100509Informations de copyright
© 2022 The Authors.
Déclaration de conflit d'intérêts
RJ has research collaborations with Takeda and Yaqrit and consults for Yaqrit. RJ is the founder of Yaqrit Limited, which is developing UCL inventions for treatment of patients with cirrhosis. RJ is an inventor of ornithine phenylacetate, which was licensed by UCL to Mallinckrodt. He is also the inventor of Yaq-001, DIALIVE, and Yaq-005, the patents for which have been licensed by his University into a UCL spinout company, Yaqrit Ltd. All other authors report no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details.
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