Chronic hyperammonemia induces peripheral inflammation that leads to cognitive impairment in rats: Reversed by anti-TNF-α treatment

J Hepatol. 2020 Sep;73(3):582-592. doi: 10.1016/j.jhep.2019.01.008. Epub 2019 Jan 14.


Background & aims: Chronic hyperammonemia induces neuroinflammation which mediates cognitive impairment. How hyperammonemia induces neuroinflammation remains unclear. We aimed to assess whether: chronic hyperammonemia induces peripheral inflammation, and whether this then contributes to neuroinflammation, altered neurotransmission and impaired spatial learning - before assessing whether this neuroinflammation and impairment is reversible following hyperammonemia elimination or treatment of peripheral inflammation with anti-TNF-α.

Methods: Chronic hyperammonemia was induced by feeding rats an ammonia-containing diet. Peripheral inflammation was analyzed by measuring PGE2, TNF-α, IL-6 and IL-10. We tested whether chronic anti-TNF-α treatment improves peripheral inflammation, neuroinflammation, membrane expression of glutamate receptors in the hippocampus and spatial learning.

Results: Hyperammonemic rats show a rapid and reversible induction of peripheral inflammation, with increased pro-inflammatory PGE2, TNF-α and IL-6, followed at around 10 days by reduced anti-inflammatory IL-10. Peripheral anti-TNF-α treatment prevents peripheral inflammation induction and the increase in IL-1b and TNF-α and microglia activation in hippocampus of the rats, which remain hyperammonemic. This is associated with prevention of the altered membrane expression of glutamate receptors and of the impairment of spatial memory assessed in the radial and Morris water mazes.

Conclusions: This report unveils a new mechanism by which chronic hyperammonemia induces neurological alterations: induction of peripheral inflammation. This suggests that reducing peripheral inflammation by safe procedures would improve cognitive function in patients with minimal hepatic encephalopathy.

Lay summary: This article unveils a new mechanism by which chronic hyperammonemia induces cognitive impairment in rats: chronic hyperammonemia per se induces peripheral inflammation, which mediates many of its effects on the brain, including induction of neuroinflammation, which alters neurotransmission, leading to cognitive impairment. It is also shown that reducing peripheral inflammation by treating rats with anti-TNF-α, which does not cross the blood-brain barrier, prevents hyperammonemia-induced neuroinflammation, alterations in neurotransmission and cognitive impairment.

Keywords: Cognitive impairment; Hepatic encephalopathy; Hyperammonemia; Neuroinflammation; Peripheral inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Cognitive Dysfunction / blood
  • Cognitive Dysfunction / etiology*
  • Cognitive Dysfunction / prevention & control*
  • Disease Models, Animal
  • Hepatic Encephalopathy / drug therapy
  • Hepatic Encephalopathy / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hyperammonemia / complications*
  • Inflammation / drug therapy
  • Inflammation / etiology
  • Inflammation / metabolism
  • Infliximab / administration & dosage*
  • Male
  • Memory / drug effects
  • Rats
  • Rats, Wistar
  • Spatial Learning / drug effects
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / blood


  • Anti-Inflammatory Agents
  • Tumor Necrosis Factor-alpha
  • Infliximab