Induction of systemic oxidative stress leads to brain oedema in portacaval shunted rats
Article [Accepted Manuscript]
Abstract(s)
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.
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