Bile-duct ligation renders the brain susceptible to hypotension-induced neuronal degeneration: Implications of ammonia

J Neurochem. 2021 May;157(3):561-573. doi: 10.1111/jnc.15290. Epub 2021 Feb 13.


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.

Keywords: bile duct-ligation; hypotension; liver transplant; minimal hepatic encephalopathy; neuronal death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonia / blood
  • Ammonia / metabolism*
  • 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
  • Neurodegenerative Diseases / pathology*
  • Neurodegenerative Diseases / psychology
  • Neurons / pathology*
  • Ornithine / analogs & derivatives
  • Ornithine / therapeutic use
  • Rats
  • Rats, Sprague-Dawley


  • Antigens, Nuclear
  • Nerve Tissue Proteins
  • Rbfox3 protein, rat
  • Ammonia
  • ornithine phenylacetate
  • Ornithine
  • Casp3 protein, rat
  • Caspase 3

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