Interaction of oxidative stress, astrocyte swelling and cerebral ammonia toxicity.
OBJECTIVE
Description of the role of oxidative stress in the pathogenesis of cerebral ammonia toxicity and hepatic encephalopathy.


RESULTS
Ammonia plays a key role in the pathogenesis of hepatic encephalopathy, which manifests as a neuropsychiatric syndrome accompanying acute and chronic liver failure. One consequence of ammonia action on the brain is astrocyte swelling, which triggers the generation of oxidative/nitrosative stress at the level of NADPH oxidase, nitric oxide synthases and the mitochondria. A self-amplifying signaling loop between oxidative stress and astrocyte swelling has been proposed. Consequences of the ammonia-induced oxidative/nitrosative stress response are protein modifications through nitration of tyrosine residues and oxidation of astrocytic and neuronal RNA. Nitrosative stress also mobilizes zinc from intracellular stores with impact on gene expression. These alterations may at least in part mediate cerebral ammonia toxicity through disturbances of intracellular and intercellular signaling and of synaptic plasticity.


CONCLUSIONS
Oxidative/nitrosative stress and a low-grade cerebral edema as key events in the pathogenesis of ammonia toxicity and hepatic encephalopathy may offer potential new strategies for treatment. Ammonia-induced oxidation of RNA and proteins may impair postsynaptic protein synthesis, which is critically involved in learning and memory consolidation. RNA oxidation offers a novel explanation for multiple disturbances of neurotransmitter systems and gene expression and the cognitive deficits observed in hepatic encephalopathy.
Häussinger
Dieter
D
Heinrich-Heine-University Düsseldorf, Clinic for Gastroenterology, Hepatology, and Infectiology, Düsseldorf, Germany. haeussin@uni-duesseldorf.de
Görg
Boris
B
D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D001921:Brain / Q000378:metabolism*; D001929:Brain Edema / Q000139:chemically induced / Q000378:metabolism*; D015870:Gene Expression; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D015538:Nitrosation; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D011506:Proteins; D014443:Tyrosine; D012313:RNA; D000641:Ammonia; D015032:Zinc