Induction of systemic oxidative stress leads to brain oedema in portacaval shunted rats

Liver Int. 2014 Oct;34(9):1322-9. doi: 10.1111/liv.12414. Epub 2013 Dec 17.


Background & aims: The pathogenesis of hepatic encephalopathy (HE) is multifactorial and often associated with the development of brain oedema. In addition to ammonia playing a central role, systemic oxidative stress is believed to aggravate the neuropsychological effects of ammonia in patients with chronic liver disease (CLD). The aim of this study was to (i) induce systemic oxidative stress in hyperammonaemic portacaval anastomosed (PCA) rats by inhibiting the antioxidant glutathione using Dimethyl maleate (DEM) and (ii) investigate whether a synergistic relationship between ammonia and oxidative stress contributes to the pathogenesis of brain oedema in CLD.

Methods: Four-week PCA and sham-operated rats received DEM (0.4-4 mg/kg/day) for the last 10 days before sacrifice when oxidative stress markers [reactive oxygen species (ROS) and malondialdehyde (MDA)] were assessed in blood and frontal cortex. Brain water content was measured using a specific gravimetric technique.

Results: Dimethyl maleate induced an increase in ROS and MDA in the blood, but not in the brain, of the PCA rats, compared with non-treated PCA rats. This was accompanied with an increase in brain water content (PCA+DEM: 78.45 ± 0.13% vs. PCA: 77.38 ± 0.11%, P < 0.001). Higher doses of DEM induced systemic oxidative stress in sham-operated controls, but brain oedema did not develop.

Conclusions: Dimethyl maleate provoked systemic, not central, oxidative stress in PCA rats, resulting in the development of brain oedema. Independently, hyperammonaemia and systemic oxidative stress do not precipitate brain oedema; therefore, our findings sustain that a synergistic effect between hyperammonaemia and systemic oxidative stress is responsible for the development of brain oedema in HE.

Keywords: brain oedema; dimethyl maleate; hepatic encephalopathy; oxidative stress; portacaval shunt.

MeSH terms

  • Ammonia / toxicity*
  • Analysis of Variance
  • Animals
  • Biomarkers / metabolism*
  • Brain Edema / etiology
  • Brain Edema / physiopathology*
  • End Stage Liver Disease / complications*
  • Glutathione / antagonists & inhibitors
  • Hepatic Encephalopathy / etiology
  • Hepatic Encephalopathy / physiopathology*
  • Male
  • Maleates / administration & dosage
  • Maleates / pharmacology*
  • Malondialdehyde / blood
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Portacaval Shunt, Surgical
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / blood


  • Biomarkers
  • Maleates
  • Reactive Oxygen Species
  • Malondialdehyde
  • Ammonia
  • Glutathione
  • dimethyl maleate