Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy

Dedicated to Prof. Dr. C.R. Murphy.
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Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome during the course of acute or chronic liver disease. It is functional in nature, potentially reversible and precipitated by rather heterogeneous factors. Current evidence suggests that HE is the consequence of a low grade chronic glial edema with subsequent alterations of glioneuronal communication. Other lines of evidence support a role of NMDA receptor activation and oxidative/nitrosative stress in the pathogenesis of HE. Different HE-precipitating factors, such as ammonia, benzodiazepines, inflammatory cytokines and hyponatremia induce or aggravate astrocyte swelling and additionally increase oxidative/nitrosative stress and protein tyrosine nitration. Recent findings suggest a close interrelation between astrocyte swelling, NMDA receptor signaling, glutamate, oxidative stress and nitric oxide, which may result in mutual amplification of swelling and oxidative stress. Via such an autoamplificatory loop astrocytes may integrate HE-relevant signals triggered by HE-precipitating factors. This review focuses on the involvement of astrocyte swelling in protein tyrosine nitration and potential consequences in the setting of HE.

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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