期刊
LIVER INTERNATIONAL
卷 34, 期 9, 页码 1322-1329出版社
WILEY
DOI: 10.1111/liv.12414
关键词
hepatic encephalopathy; oxidative stress; brain oedema; portacaval shunt; dimethyl maleate
Background & AimsThe 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. MethodsFour-week PCA and sham-operated rats received DEM (0.4-4mg/kg/day) for the last 10days 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. ResultsDimethyl 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: 78.450.13% 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. ConclusionsDimethyl 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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