Elevated dopamine induces minimal hepatic encephalopathy by activation of astrocytic NADPH oxidase and astrocytic protein tyrosine nitration.

BACKGROUND: We previously demonstrated that dopamine (DA) overload may be a key mechanism behind development of minimal hepatic encephalopathy (MHE) in rats. It has been shown that low-grade cerebral oedema and oxidative stress play important roles in the pathogenesis of MHE. In the current study, DA-triggered oxidative injury in cerebral cortex was studied.

METHODS: An MHE rat model was used. DA was injected intracerebroventricularly (i.c.v.) into rats and added to primary cortical astrocytes (PCAs). Immunoblotting, immunoprecipitation and immunostaining were conducted after DA injection.

RESULTS: Cognitive impairment and cerebral edema were observed in MHE rats and rats injected with 10 μg DA. Astrocyte swelling was increased by DA. Astrocytic protein tyrosine nitration (PTN) was induced by DA. DA-induced PTN was insensitive to l-NMMA but was blunted by apocynin, superoxide dismutase, catalase and uric acid. Exposure to DA substantially increased levels of astrocytic NADPH oxidase subunits and induced p47(phox) phosphorylation and reactive oxygen species production but decreased the expression and activity of neuronal-type nitric oxide synthase (nNOS).

CONCLUSIONS: PTN induced by DA, which was attributed to NADPH oxidase and not to nNOS, may alter astrocyte function and thereby contribute to the precipitation of MHE episodes.