Osmotic and oxidative/nitrosative stress in ammonia toxicity and hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of acute or chronic liver failure. Currently, HE in cirrhotic patients is seen as a clinical manifestation of a low grade cerebral edema which exacerbates in response to a variety of precipitating factors after an ammonia-induced exhaustion of the volume-regulatory capacity of the astrocyte. Astrocyte swelling triggers a complex signaling cascade which relies on NMDA receptor activation, elevation of intracellular Ca(2+) concentration and prostanoid-driven glutamate exocytosis, which result in increased formation of reactive nitrogen and oxygen species (RNOS) through activation of NADPH oxidase and nitric oxide synthase. Since RNOS in turn promote astrocyte swelling, a self-amplifying signaling loop between osmotic- and oxidative stress ensues, which triggers a variety of downstream consequences. These include protein tyrosine nitration (PTN), oxidation of RNA, mobilization of zinc, alterations in intra- and intercellular signaling and multiple effects on gene transcription. Whereas PTN can affect the function of a variety of proteins, such as glutamine synthetase, oxidized RNA may affect local protein synthesis at synapses, thereby potentially interfering with protein synthesis-dependent memory formation. PTN and RNA oxidation are also found in post mortem human cerebral cortex of cirrhotic patients with HE but not in those without HE, thereby confirming a role for oxidative stress in the pathophysiology of HE. Evidence derived from animal experiments and human post mortem brain tissue also indicates an up-regulation of microglia activation markers in the absence of increased synthesis of pro-inflammatory cytokines. However, the role of activated microglia in the pathophysiology of HE needs to be worked out in more detail. Most recent observations made in whole genome micro-array analyses of post mortem human brain tissue point to a hitherto unrecognized activation of multiple anti-inflammatory signaling pathways.