Abnormal brain oxygen homeostasis in an animal model of liver disease.
Détails
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_C7D897DAC4C2
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Abnormal brain oxygen homeostasis in an animal model of liver disease.
Périodique
JHEP reports
ISSN
2589-5559 (Electronic)
ISSN-L
2589-5559
Statut éditorial
Publié
Date de publication
08/2022
Peer-reviewed
Oui
Volume
4
Numéro
8
Pages
100509
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: 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 <sub>2</sub> was found to be normal in BDL animals.
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.
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 <sub>2</sub> was found to be normal in BDL animals.
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.
Mots-clé
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
Pubmed
Web of science
Open Access
Oui
Création de la notice
02/08/2022 14:38
Dernière modification de la notice
23/01/2024 8:34