Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy
Introduction
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome during the course of acute or chronic liver disease (Hazell and Butterworth, 1999, Häussinger et al., 2000, Häussinger et al., 2003). It is functional in nature, potentially reversible and precipitated by rather heterogeneous factors such as bleeding and high protein diet, hyponatremia, sedatives and inflammation. At the neurophysiological level HE is characterized by a disturbance of oscillatory networks with a shift of cortico-cortical and cortico-muscular electrical coupling to low frequencies, which may explain the cognitive and fine motor deficits, respectively (Timmermann et al., 2002, Timmermann et al., 2003, Zafiris et al., 2004). Recent data suggest that HE in liver cirrhosis is the clinical manifestation of a low grade chronic cerebral edema, which transiently can exacerbate under the influence of precipitating factors (Häussinger et al., 1994, Häussinger et al., 2000). In this context astrocytes play a dominant role, which are a major site of ammonia detoxication in HE (Martinez-Hernandez et al., 1977, Lockwood et al., 1991) and whose functional alterations under the influence of hydration changes and neurotoxins may alter glio-neuronal communication (Norenberg, 1996).
Section snippets
Astrocyte swelling in hepatic encephalopathy
Cerebral detoxication of ammonia is performed by the astrocytes, which represent the predominant cellular compartment in brain expressing the glutamine synthetase (Martinez-Hernandez et al., 1977). Hyperammonemia induces astrocyte swelling due to osmotic water infux following intracellular glutamine accumulation. Astrocyte swelling (cytotoxic brain edema), occurs in the absence of a clinically overt increase of intracranial pressure even in the subclinical stage of HE in cirrhotic patients (
NMDA receptors and nitric oxide in HE
Recent work suggested an important contribution of NMDA receptor activation and oxidative and nitrosative stress in acute HE (e.g. reviewed by Blei and Larsen, 1999, Monfort et al., 2002, Norenberg, 2003). It was hypothesized (Blei and Larsen, 1999) that elevation of extracellular glutamate due to astrocyte swelling induces overstimulation of the neuronally expressed N-methyl-d-aspartate (NMDA) receptors. NMDA receptor activation increases the intracellular Ca2+ concentration, leading to a Ca2+
Astrocyte swelling increases oxidative stress and protein tyrosine nitration
Hypoosmotic treatment of cultured astrocytes is a frequently used experimental paradigm for studies on the effects of astrocyte swelling on signal transduction and metabolism (Kimelberg, 1995). This model was used for examining the impact of astrocyte swelling for the generation of oxidative stress and its consequences. Hypoosmotic swelling of cultured rat astrocytes resulted in an almost immediate oxidative stress response and increased tyrosine nitration of distinct proteins (Schliess et al.,
Astroglial protein tyrosine nitration in response to ammonia and benzodiazepines and its functional relevance
Similar to hypoosmotic astrocyte swelling (Schliess et al., 2004), ammonia (Schliess et al., 2002), benzodiazepines (Görg et al., 2003) and inflammatory cytokines such as tumor necrosis factor-α, interferons α and γ (Görg et al., in preparation) increase protein tyrosine nitration (PTN) in cultured rat astrocytes. At the level of distinct proteins, a synergistic action of ammonia and diazepam on tyrosine nitration was observed, further supporting a role of PTN in the development of HE. Whereas
Potential relevance of protein tyrosine nitration for HE
Astroglial PTN was not only shown in cultured astrocytes, but also in vivo (Schliess et al., 2002, Görg et al., 2003). Elevated levels of PTN were found in the cerebral cortex from PCA rats (Schliess et al., 2002), which represent a model for chronic hyperammonemia (Butterworth et al., 1988, Chamuleau, 1996). Here, immunoprecipitated 3′-tyrosine-nitrated proteins were enriched with glutamine synthetase (Schliess et al., 2002), indicating that PTN in response to PCA involves astrocytes, because
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