Bile-duct ligation renders the brain susceptible to hypotension-induced neuronal degeneration: Implications of ammonia.
Ammonia
/ blood
Animals
Antigens, Nuclear
/ metabolism
Anxiety
/ psychology
Apoptosis
Behavior, Animal
Bile Ducts
Caspase 3
/ metabolism
Cerebrovascular Circulation
/ drug effects
Disease Models, Animal
Hepatic Encephalopathy
/ pathology
Hyperammonemia
Hypotension
/ pathology
Ligation
Male
Nerve Tissue Proteins
/ metabolism
Neurodegenerative Diseases
/ metabolism
Neurons
/ pathology
Ornithine
/ analogs & derivatives
Rats
Rats, Sprague-Dawley
bile duct-ligation
hypotension
liver transplant
minimal hepatic encephalopathy
neuronal death
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
22
12
2020
received:
04
06
2020
accepted:
29
12
2020
pubmed:
1
1
2021
medline:
22
6
2021
entrez:
31
12
2020
Statut:
ppublish
Résumé
Hepatic encephalopathy (HE) is a debilitating neurological complication of cirrhosis. By definition, HE is considered a reversible disorder, and therefore HE should resolve following liver transplantation (LT). However, persisting neurological complications are observed in as many as 47% of LT recipients. LT is an invasive surgical procedure accompanied by various perioperative factors such as blood loss and hypotension which could influence outcomes post-LT. We hypothesize that minimal HE (MHE) renders the brain frail and susceptible to hypotension-induced neuronal cell death. Six-week bile duct-ligated (BDL) rats with MHE and respective SHAM-controls were used. Several degrees of hypotension (mean arterial pressure of 30, 60 and 90 mm Hg) were induced via blood withdrawal from the femoral artery and maintained for 120 min. Brains were collected for neuronal cell count and apoptotic analysis. In a separate group, BDL rats were treated for MHE with the ammonia-lowering strategy ornithine phenylacetate (OP; MNK-6105), administered orally (1 g/kg) for 3 weeks before induction of hypotension. Hypotension 30 and 60 mm Hg (not 90 mm Hg) significantly decreased neuronal marker expression (NeuN) and cresyl violet staining in the frontal cortex compared to respective hypotensive SHAM-operated controls as well as non-hypotensive BDL rats. Neuronal degeneration was associated with an increase in cleaved caspase-3, suggesting the mechanism of cell death was apoptotic. OP treatment attenuated hyperammonaemia, improved anxiety and activity, and protected the brain against hypotension-induced neuronal cell death. Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension-induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post-transplant and that treating for MHE pre-LT might reduce this risk.
Substances chimiques
Antigens, Nuclear
0
Nerve Tissue Proteins
0
Rbfox3 protein, rat
0
Ammonia
7664-41-7
ornithine phenylacetate
9D6YZ105SN
Ornithine
E524N2IXA3
Casp3 protein, rat
EC 3.4.22.-
Caspase 3
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
561-573Subventions
Organisme : CIHR
ID : MOP 130556
Pays : Canada
Informations de copyright
© 2020 International Society for Neurochemistry.
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