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Patients with liver disease with overt or minimal hepatic encephalopathy show impaired intellectual capacity. The underlying molecular mechanism remains unknown. Rats with portacaval anastomosis or with hyperammonemia without liver failure also show impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanine monophosphate (glutamate-NO-cGMP) pathway in brain. We hypothesized that pharmacological manipulation of the pathway in order to increase cGMP content could restore learning ability. We show by in vivo brain microdialysis that chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, normalizes the function of the glutamate-NO-cGMP pathway and extracellular cGMP in brain in vivo in rats with portacaval anastomosis or with hyperammonemia. Moreover, sildenafil restored the ability of rats with hyperammonemia or with portacaval shunts to learn a conditional discrimination task.

One of the neurological alterations in patients with minimal or overt hepatic encephalopathy is cognitive impairment. This impairment is reproduced in rats with chronic liver failure due to portacaval shunt (PCS). These rats show decreased ability to learn a conditional discrimination task in a Y-maze, likely due to reduced function of the glutamate-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in brain. It has been proposed that inflammation exacerbates the neuropsychological alterations induced by hyperammonemia, suggesting that inflammation-associated alterations may contribute to cognitive impairment in hepatic encephalopathy. This study assessed whether treatment with an anti-inflammatory drug, ibuprofen, is able to restore the function of the glutamate-NO-cGMP pathway in cerebral cortex in brain in vivo and/or learning ability in PCS rats. We show that PCS rats have increased levels of interleukin-6 and increased activities of cyclooxygenase and of inducible NO synthase in cerebral cortex, indicating the presence of inflammation. Chronic treatment with ibuprofen normalizes cyclooxygenase and inducible NO synthase activities but not interleukin-6 levels. Moreover, ibuprofen normalizes the function of the glutamate-NO-cGMP pathway in cerebral cortex in vivo and completely restores the ability of rats with chronic liver failure to learn the Y-maze task. Learning ability is also impaired 1 in rats with chronic liver failure due to portacaval shunt (PCS). In this model the function of the glutamate-NO-cGMP pathway is impaired in cerebellum 2 and cerebral cortex 3 in vivo. Moreover, increasing cGMP in brain by administration of phosphodiesterase inhibitors restores learning ability of PCS rats, 1 indicating that reduced cGMP formation is responsible for impaired learning. However, the factors and mechanisms by which chronic liver failure impairs the function of this pathway and learning ability remain unclear.Shawcross et al. 4 proposed that inflammation exacerbates the neuropsychological alterations induced by hyperammonemia. Chung et al. 5 also showed that a nonsteroidal anti-inflammatory drug (NSAID), indomethacin, prevents the development of ammonia-induced brain edema in rats after portacaval anastomosis. These reports support the idea that hyperammonemia and inflammation cooperate in the cerebral alterations present in hepatic encephalopathy. There is also increasing evidence that inflammatory mechanisms are involved in the cognitive impairment in patients with Alzheimer's disease. Epidemiologic studies show that patients (e.g., with arthritis) treated with anti-inflammatory drugs such

Studies of the pathogenesis of hepatic encephalopathy are hampered by the lack of a satisfactory animal model. We examined the neurological features of rats after bile duct ligation fed a hyperammonemic diet (BDL؉HD). Six groups were studied: sham, sham pair-fed, hyperammonemic, bile duct ligation (BDL), BDL pair fed, and BDL؉HD. The BDL؉HD rats were made hyperammonemic via an ammonia-containing diet that began 2 weeks after operation. One week later, the animals were sacrificed. BDL؉HD rats displayed an increased level of cerebral ammonia and neuroanatomical characteristics of hepatic encephalopathy (HE), including the presence of type II Alzheimer astrocytes. Both BDL and BDL؉HD rats showed activation of the inflammatory system. BDL؉HD rats showed an increased amount of brain glutamine, a decreased amount of brain myo-inositol, and a significant increase in the level of brain water. In coordination tests, BDL؉HD rats showed severe impairment of motor activity and performance as opposed to BDL rats, whose results seemed only mildly affected. In conclusion, the BDL؉HD rats displayed similar neuroanatomical and neurochemical characteristics to human HE in liver cirrhosis. Brain edema and inflammatory activation can be detected under these circumstances. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). H epatic encephalopathy (HE) is a severe neuropsychiatric complication in both acute and chronic liver failure. Although the pathophysiology of this disorder is incompletely understood, there is agreement on the important role of neurotoxins in its development, especially ammonia. 1 Neuropathologically, HE in chronic liver disease is characterized by astrocytic rather than neuronal changes. 2 Histopathology studies of brain sections from patients with cirrhosis who died in hepatic coma show the presence of changes known as Alzheimer type II astrocytosis. These astrocytes display a specific characteristic of swollen cytoplasm containing a large pale nucleus, with prominent nucleolus and patches of heterochromatin associated with the nuclear envelope. 2 Recently, a new pathophysiological hypothesis has been developed, emphasizing the role of low-grade brain edema in the pathogenesis of HE in chronic liver disease. 3 Following this theoretical model, the presence of a lowgrade astrocyte swelling could have important functional consequences despite the absence of clinically overt increases of intracranial pressure. 3

Patients with hepatic encephalopathy (HE) may present different neurological alterations including impaired cognitive function and altered motor activity and coordination. HE may lead to coma and death. Many of these neurological alterations are the consequence of altered neurotransmission. Hyperammonemia is a main contributor to the alterations in neurotransmission and in neurological functions in HE. Both glutamatergic and GABAergic neurotransmission are altered in animal models of HE. We review some of these alterations, especially those alterations in glutamatergic neurotransmission responsible for some specific neurological alterations in hyperammonemia and HE: the role 1) of excessive NMDA receptors activation in death induced by acute hyperammonemia; 2) of impaired function of the glutamate-nitric oxide-cGMP pathway, associated to NMDA receptors, in cognitive impairment in chronic HE; 3) of increased extracellular glutamate and activation of metabotropic glutamate receptors in substantia nigra in hypokinesia in chronic HE. The therapeutic implications are discussed. We also review the alterations in the function of the neuronal circuits between basal ganglia-thalamus-cortex modulating motor activity and the role of sequential alterations in glutamatergic and GABAergic neurotransmission in these alterations. HE would be a consequence of altered neuronal communication due to alterations in general neurotransmission involving different neurotransmitter systems in different neurons.