Delphi-based recommendations for the management of cardiovascular comorbidities in patients with psoriatic arthritis and moderate-to-severe psoriasis.

The aim of this study was to generate practical recommendations to assist rheumatologists and dermatologists in the management of cardiovascular (CV) comorbidities in patients with moderate-to-severe psoriasis (MS-PSO) and psoriatic arthritis (PsA). A two-round Delphi study was conducted. A panel of experts rated their agreement with a set of statements (n = 52) on a nine-point Likert scale (1 = totally disagree; 9 = totally agree). Statements were classified as inappropriate (median 1-3), irrelevant (median 4-6) or appropriate (median 7-9). Consensus was established when at least two-thirds of the panel responded with a score within any one range. A total of 25 experts, 60% rheumatologists and 40% dermatologists, participated in two consultation rounds. There was overall unanimity on the appropriateness of an initial assessment for CV risk factors in all patients with MS-PSO and PsA. Most panelists (88.0%) also supported the evaluation of patients' psychological and physical status. Additionally, most panelists (72.2%) agreed on a novel sequential approach for the management of CV comorbidities. This sequence starts with the assessment of hypertension, diabetes and dyslipidemia along with the identification of depression and anxiety disorders. Once these factors are under control, smoking cessation programs might be initiated. Finally, if patients have not met weight loss goals with lifestyle modifications, they should receive specialized treatment for obesity. This study has drawn up a set of practical recommendations that will facilitate the management of CV comorbidities in patients with MS-PSO and PsA.

Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats.

Patients with liver cirrhosis may present hepatic encephalopathy with a wide range of neurological disturbances and alterations in sleep quality and in the sleep-wake circadian rhythm. Hyperammonemia is a main contributor to the neurological alterations in hepatic encephalopathy. We have assessed, in an animal model of chronic hyperammonemia without liver failure, the effects of hyperammonemia per se on the circadian rhythms of motor activity, temperature, and plasma levels of adrenal corticosteroid hormones. Chronic hyperammonemia alters the circadian rhythms of locomotor activity and of cortisol and corticosterone levels in blood. Different types of motor activity are affected differentially. Hyperammonemia significantly alters the rhythm of spontaneous ambulatory activity, reducing strongly ambulatory counts and slightly average velocity during the night (the active phase) but not during the day, resulting in altered circadian rhythms. In contrast, hyperammonemia did not affect wheel running at all, indicating that it affects spontaneous but not voluntary activity. Vertical activity was affected only very slightly, indicating that hyperammonemia does not induce anxiety. Hyperammonemia abolished completely the circadian rhythm of corticosteroid hormones in plasma, completely eliminating the peaks of cortisol and corticosterone present in control rats at the start of the dark period. The data reported show that chronic hyperammonemia, similar to that present in patients with liver cirrhosis, alters the circadian rhythms of corticosteroid hormones and of motor activity. This suggests that hyperammonemia would be a relevant contributor to the alterations in corticosteroid hormones and in circadian rhythms in patients with liver cirrhosis.

Neuroinflammation contributes to hypokinesia in rats with hepatic encephalopathy: ibuprofen restores its motor activity.

Patients with hepatic encephalopathy show altered motor function, psychomotor slowing, and hypokinesia, which are reproduced in rats with portacaval shunts (PCS). Increased extracellular glutamate in substantia nigra pars reticulata (SNr) is responsible for hypokinesia in PCS rats. The mechanisms by which liver failure leads to increased extracellular glutamate in SNr remain unclear. Inflammation seems to act synergistically with hyperammonemia to induce neurological alterations in hepatic encephalopathy. It is therefore possible that inflammation-associated alterations may contribute to motor alterations in hepatic encephalopathy. The aim of this work was to assess whether treatment with an antiinflammatory, ibuprofen, is able to normalize extracellular glutamate in SNr and/or to improve hypokinesia in PCS rats. The amounts of the glutamate transporters GLT-1 and EAAC-1 are reduced by 26% and 32%, respectively, in SNr of PCS rats. This reduction is associated with a tenfold increase in extracellular glutamate in SNr and a reduction in motor activity. Chronic treatment with 30 mg/kg ibuprofen completely normalizes the amount of GLT-1 and EAAC-1 and significantly reduces (by 53%) extracellular glutamate in SNr of PCS rats. Moreover, ibuprofen, at 15 or 30 (but not at 5) mg/kg/day, completely eliminates hypokinesia, restoring normal motor activity. This supports the idea that inflammation is a main contributor to the induction of hypokinesia in hepatic encephalopathy. Moreover, these data point to the possible therapeutic utility of decreasing inflammation, by safe procedures, in the treatment of the motor deficits in patients with hepatic encephalopathy.

IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy.

BACKGROUND AND AIMS: Patients with liver cirrhosis may present minimal hepatic encephalopathy (MHE) that can be unveiled using specific neuropsychologic examination. Evaluation of MHE in cirrhotic patients might have prognostic value. The psychometric HE score (PHES) has been recommended as the "gold standard" in the diagnosis of MHE. It has been proposed that critical flicker frequency (CFF) analysis would be useful for easier detection of MHE. It would also be useful to have some peripheral parameter that could reflect the presence of MHE. It has been recently proposed that inflammation-associated alterations and hyperammonemia may cooperate in the induction of hepatic encephalopathy. The aim of the present work was to assess whether there is a correlation between the alterations in parameters reflecting inflammation, hyperammonemia, and the presence of MHE. METHODS: We have studied in 55 patients with liver cirrhosis and 26 controls the performance in the PHES battery and the CFF, ammonia, and some interleukins (ILs) as inflammatory markers. RESULTS: IL-6 and IL-18 were significantly higher (2.5-fold and 2.2-fold, respectively) in patients with MHE than in those without MHE. There were significant correlations between IL-6 or IL-18 levels and PHES score and CFF. Moreover, all patients with MHE had IL-6 levels higher than 11 ng/mL, whereas all patients without MHE had IL-6 levels lower than 11 ng/mL. CONCLUSIONS: Inflammatory alterations related with IL-6 and IL-18 may contribute to MHE. Serum concentration of IL-6 and IL-18 may be useful to discriminate cirrhotic patients with and without MHE.

Developmental exposure to polychlorinated biphenyls PCB153 or PCB126 impairs learning ability in young but not in adult rats.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants present in the food chain and in human blood and milk. Exposure to PCBs during pregnancy and lactation leads to cognitive impairment in children. The underlying mechanisms remain unclear. Some PCBs are endocrine disrupters. The aim of this work was to assess whether exposure of rats to PCB126 (dioxin-like) or PCB153 (non-dioxin-like) during pregnancy and lactation affects the ability of the pups to learn a Y maze conditional discrimination task and/or the function of the glutamate-nitric oxide (NO)-cGMP pathway in brain in vivo when the rats are young (3 months) or adult (7-8 months). After finishing the learning experiments, the function of the pathway was analysed in the same rats by in vivo brain microdialysis. The results obtained show that perinatal exposure to PCB153 or PCB126: (1) impairs learning ability in young but not in adult rats, (2) impairs the glutamate-NO-cGMP pathway function in cerebellum in vivo in young but not in adult rats and (3) affect these parameters in males and females similarly. PCB126 is around 10 000-fold more potent than PCB153. In control rats the function of the glutamate-NO-cGMP pathway and learning ability are lower in adult than in young rats. These age-related differences are not present in rats exposed to PCBs. The impairment of the glutamate-NO-cGMP pathway function induced at young age by developmental exposure to the PCBs could be one of the mechanisms contributing to the cognitive impairment found in children whose mothers ingested PCB-contaminated food during pregnancy and lactation.

Activation of soluble guanylate cyclase by nitric oxide in lymphocytes correlates with minimal hepatic encephalopathy in cirrhotic patients.

Patients with liver cirrhosis with normal neurological and mental status examination may present minimal forms of hepatic encephalopathy, showing intellectual function impairment that cannot be detected through general clinical examination but can be unveiled using specific neuropsychological or neurophysiological examination. Evaluation of minimal hepatic encephalopathy (MHE) in cirrhotic patients would have prognostic value. The psychometric hepatic encephalopathy score (PHES) has been recommended as the "gold standard" in the diagnosis of MHE. Altered modulation of cyclic GMP (cGMP) levels in the brain seems to be responsible for the impairment of some types of cognitive function in liver disease. In animal models of liver disease, some of the alterations in modulation of cGMP levels in the brain are reproduced in lymphocytes. The aim of the present work was to assess whether there is a correlation between the alterations in different parameters involved in modulation of cGMP levels and the presence of MHE in patients with liver disease. We studied in 46 patients with liver cirrhosis and 26 controls the performance in the PHES battery of psychometric tests and the critical flicker frequency (CFF), the concentration of cGMP in plasma and lymphocytes, activation of guanylate cyclase by nitric oxide (NO) in lymphocytes, and several parameters likely involved in altered cGMP homeostasis in liver disease such as ammonia, NO metabolites, and atrial natriuretic peptide (ANP). Activation of guanylate cyclase by NO in lymphocytes and cGMP in plasma were higher and CFF lower in patients with MHE than in patients without MHE. Ammonia, ANP, and metabolites of NO were higher in patients than in controls but were no different in patients with or without MHE. Alteration in activation of guanylate cyclase by NO in lymphocytes correlates with PHES performance, CFF, and ammonia levels. This suggests that altered modulation of guanylate cyclase by NO in lymphocytes would reflect a parallel alteration in the brain occurring in patients with MHE that would be involved in their cognitive impairment.

The function of the glutamate-nitric oxide-cGMP pathway in brain in vivo and learning ability decrease in parallel in mature compared with young rats.

Aging is associated with cognitive impairment, but the underlying mechanisms remain unclear. We have recently reported that the ability of rats to learn a Y-maze conditional discrimination task depends on the function of the glutamate-nitric oxide-cGMP pathway in brain. The aims of the present work were to assess whether the ability of rats to learn this task decreases with age and whether this reduction is associated with a decreased function of the glutamate-nitric oxide-cGMP pathway in brain in vivo, as analyzed by microdialysis in freely moving rats. We show that 7-mo-old rats need significantly more (192 +/- 64%) trials than do 3-mo-old rats to learn the Y-maze task. Moreover, the function of the glutamate-nitric oxide-cGMP pathway is reduced by 60 +/- 23% in 7-mo-old rats compared with 3-mo-old rats. The results reported support the idea that the reduction in the ability to learn the Y-maze task (and likely other types of learning) of mature compared with young rats would be a consequence of reduced function of the glutamate-nitric oxide-cGMP pathway.

Role of extracellular cGMP and of hyperammonemia in the impairment of learning in rats with chronic hepatic failure. Therapeutic implications.

Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with chronic or acute liver disease. We review here some recent advances in the study, in animal models, of the mechanisms involved in the impairment in intellectual function in hepatic encephalopathy. These studies show that the function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in rats with chronic hyperammonemia or liver failure and from patients died in hepatic encephalopathy. This impairment leads to a reduced extracellular concentration of cGMP in the cerebellum and is associated with reduced learning ability in these animal models. Moreover, learning ability of hyperammonemic rats was restored by increasing cGMP by: (1) continuous intracerebral administration of zaprinast, an inhibitor of the cGMP-degrading phosphodiesterase, (2) chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that crosses the blood-brain barrier and (3) continuous intracerebral administration of cGMP. The data summarized indicate that impairment of learning ability in rats with chronic liver failure or hyperammonemia is due to impairment of the glutamate-nitric oxide-cGMP pathway. Moreover, increasing extracellular cGMP by pharmacological means may be a new therapeutic approach to improve cognitive function in patients with hepatic encephalopathy.

Rats with minimal hepatic encephalopathy show reduced cGMP-dependent protein kinase activity in hypothalamus correlating with circadian rhythms alterations.

Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light.

Gender differential effects of developmental exposure to methyl-mercury, polychlorinated biphenyls 126 or 153, or its combinations on motor activity and coordination.

Polychlorinated biphenyls (PCBs) and methylmercury (MeHg) are persistent organic pollutants accumulating in the food chain. Pre- and neonatal exposure to these neurotoxicants may affect brain development and lead to long-lasting alterations in cerebral function, which can result in motor alterations in youth and/or adulthood. Some neurotoxicants induce gender specific effects. The aims of the present work were to: (1) assess the effects of developmental exposure to MeHg, PCB 153 or PCB 126 on spontaneous locomotor and vertical activity and motor coordination when the rats are 2-month old; (2) assess whether perinatal exposure to combinations of MeHg with PCB153 or PCB126 alter the effects of the individual neurotoxicants; (3) follow the progression of motor alterations when the rats are 3-, 5- and 7-month old; (4) assess if the effects are similar or different in males and females. Pregnant rats were treated with MeHg (0.5mg/kgday); PCB126 (100ng/kgday) or PCB153 (1mg/kgday) or with combinations of MeHg with each PCB, administered in food from gestational day 7 until weaning at post-natal day 21. PCB 126 impaired motor coordination at 2 months in males but not in females. PCB 153 impaired coordination both in males and females. Combinations of MeHg with PCB153 or PCB126 did not affect motor coordination, indicating that MeHg counteracts the effects of the PBCs. The combination of MeHg and PCB153 induces hypolocomotion at 2 months but hyperactivity at 7 months while the individual compounds did not induce any effect. PCB126 induced gender selective effects, reducing locomotor activity at 2 months in females but not in males. The combination of MeHg and PCB126 behaves as PCB126 alone. All compounds and combinations tested induce gender-selective alterations in vertical activity. The effects on locomotor and vertical activity change with age in the same rats. At 2 months all compounds and combinations reduce vertical activity in females but not in males. At 7 months all treatments induced hyperactivity both in males and females, except MeHg+PCB126. In conclusion, the results show that: (a) many motor alterations induced by most compounds are different in males and females; (b) mixtures of MeHg with PCBs 153 or 126 induce different effects that the individual compounds; (c) different types of motor activity (spontaneous locomotion, vertical activity and motor coordination) are affected differently by the same neurotoxicant or mixture; and (d) the effects on locomotor and specially on vertical activity change with the age of the rat. Most compounds reduce activity at youth (2 months) and induce hyperactivity at adulthood (5-7 months). The change from hypo- to hyperactivity occurs earlier in males.

Transport of AMPA receptors during long-term potentiation is impaired in rats with hepatic encephalopathy.

Cognitive function is impaired in patients with hepatic encephalopathy. Learning ability is also impaired in rats with hepatic encephalopathy due to portacaval shunts. Long-term potentiation (LTP) in hippocampus, considered the basis of some forms of learning and memory, is impaired in rats with portacaval shunt. We analyzed the mechanisms by which LTP is impaired in these rats. In control rats, application of the tetanus to induce LTP increases phosphorylation of Thr286 of calcium-calmodulin dependent protein kinase II. This activates the kinase which phosphorylates the GluR1 subunit of AMPA receptors in Ser831 and induces its translocation to the post-synaptic densities. All these steps are completely prevented in rats with hepatic encephalopathy in which the tetanus does not induce phosphorylation of CaMKII or GluR1 nor translocation of this subunit to the post-synaptic membrane. This would explain the impairment in LTP in these rats.

Polychlorinated biphenyls PCB 153 and PCB 126 impair the glutamate-nitric oxide-cGMP pathway in cerebellar neurons in culture by different mechanisms.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants present in human blood and milk. Exposure to PCBs during pregnancy and lactation leads to cognitive impairment in children. Perinatal exposure to PCB 153 or PCB 126 impairs the glutamate-nitric oxide-cGMP pathway in cerebellum in vivo and learning ability in adult rats. The aims of this work were: (1) to assess whether long-term exposure of primary cultures of cerebellar neurons to PCB 153 or PCB 126 reproduces the impairment in the function of the glutamate-nitric oxide-cGMP pathway found in rat cerebellum in vivo; (2) to provide some insight on the steps of the pathway affected by these PCBs; (3) to assess whether the mechanisms of interference of the pathway are different for PCB 126 and PCB 153. Both PCB 153 and PCB 126 increase basal levels of cGMP by different mechanisms. PCB 126 increases the amount of soluble guanylate cyclase while PCB 153 does not. PCB 153 reduces the amount of calmodulin while PCB 126 does not. Also both PCBs impair the function of the glutamate-nitric oxide-cGMP pathway by different mechanisms, PCB 153 impairs nitric oxide-induced activation of soluble guanylate cyclase and increase in cGMP while PCB 126 does not. PCB 126 reduces NMDA-induced increase in calcium while PCB 153 does not. When PCB 153 and PCB 126 exhibit the same effect, PCB 126 was more potent than PCB 153, as occurs in vivo.

Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy.

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.

Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications.

Patients with liver diseases (e.g. cirrhosis) may present hepatic encephalopathy (HE), an alteration in cerebral function which is a consequence of previous failure of liver function. Patients with minimal or clinical HE present different levels of cognitive impairment. Hyperammonemia is considered a main contributor to the neurological alterations in HE. Animal models of chronic HE (e.g. rats with portacaval shunts) or of "pure" hyperammonemia also show impaired cognitive function. The studies summarized here show that the impairment of some types of cognitive function in chronic HE is due to the impaired function of the glutamate-nitric oxide-cGMP pathway in brain. Both hyperammonemia and neuroinflammation contribute to the impairment of the pathway and of cognitive function. Treatment of rats with chronic HE or hyperammonemia with inhibitors of phosphodiesterase 5 restores the function of the glutamate-nitric oxide-cGMP pathway and cGMP levels in brain as well as the ability to learn a Y maze conditional discrimination task. The same beneficial effects may be obtained by treating the rats chronically with an anti-inflammatory, ibuprofen. As the function of this pathway is also altered in brain of patients died in HE, this alteration would also contribute to cognitive impairment in patients with HE. Increasing cGMP by using inhibitors of phosphodiesterase 5 (PDE-5) or anti-inflammatories (under safe conditions) would be therefore a new therapeutic approach to improve learning and memory performance in individuals with minimal or clinical HE.

Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain.

Developing procedures to delay the mechanisms of acute liver failure-induced death would increase patients' survival by allowing time for liver regeneration or to receive a liver for transplantation. Hyperammonemia is a main contributor to brain herniation and mortality in acute liver failure (ALF). Acute ammonia intoxication in rats leads to N-methyl-D-aspartate (NMDA) receptor activation in brain. Blocking these receptors prevents ammonia-induced death. Ammonia-induced activation of NMDA receptors could contribute to ALF-induced death. If this were the case, blocking NMDA receptors could prevent or delay ALF-induced death. The aim of this work was to assess 1) whether ALF leads to NMDA receptors activation in brain in vivo and 2) whether blocking NMDA receptors prevents or delays ALF-induced death of rats. It is shown, by in vivo brain microdialysis, that galactosamine-induced ALF leads to NMDA receptors activation in brain. Blocking NMDA receptors by continuous administration of MK-801 or memantine through miniosmotic pumps affords significant protection against ALF-induced death, increasing the survival time approximately twofold. Also, when liver injury is not 100% lethal (1.5 g/kg galactosamine), blocking NMDA receptors increases the survival rate from 23 to 62%. This supports that blocking NMDA receptors could have therapeutic utility to improve survival of patients with ALF.

Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts.

UNLABELLED: 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. This supports that inflammation contributes to the cognitive impairment in hepatic encephalopathy. CONCLUSION: the results reported point to the possible therapeutic utility of decreasing inflammation in the treatment of the cognitive deficits in patients with minimal or overt hepatic encephalopathy.

Chronic liver failure in rats impairs glutamatergic synaptic transmission and long-term potentiation in hippocampus and learning ability.

Cognitive function is impaired in patients with liver disease by unknown mechanisms. Long-term potentiation (LTP) in the hippocampus is considered the basis of some forms of learning and memory. The aims of this work were to assess (i) whether chronic liver failure impairs hippocampal LTP; (ii) if this impairment may be due to alterations in glutamatergic neurotransmission, and (iii) if impairment of LTP is associated with reduced learning ability. It is shown that liver failure in Wistar rats induces the following alterations in the hippocampus; (i) alters the phosphorylation of NMDA and AMPA receptors; (ii) reduces the expression of NMDA and AMPA receptors in membranes, (iii) reduces the magnitude of excitatory postsynaptic potentials (EPSPs) induced by activation of NMDA or AMPA receptors, and (iv) impairs NMDA receptor-dependent LTP. Liver failure also impairs learning of the Morris water maze task. Impairment of glutamatergic synaptic transmission and NMDA receptor-mediated responses may be involved in the alterations of cognitive function in patients with liver disease.

Glutamate-induced activation of nitric oxide synthase is impaired in cerebral cortex in vivo in rats with chronic liver failure.

It has been proposed that impairment of the glutamate-nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in brain contributes to cognitive impairment in hepatic encephalopathy. The aims of this work were to assess whether the function of this pathway and of nitric oxide synthase (NOS) are altered in cerebral cortex in vivo in rats with chronic liver failure due to portacaval shunt (PCS) and whether these alterations are due to hyperammonemia. The glutamate-nitric oxide-cGMP pathway function and NOS activation by NMDA was analysed by in vivo microdialysis in cerebral cortex of PCS and control rats and in rats with hyperammonemia without liver failure. Similar studies were done in cortical slices from these rats and in cultured cortical neurons exposed to ammonia. Basal NOS activity, nitrites and cGMP are increased in cortex of rats with hyperammonemia or liver failure. These increases seem due to increased inducible nitric oxide synthase expression. NOS activation by NMDA is impaired in cerebral cortex in both animal models and in neurons exposed to ammonia. Chronic liver failure increases basal NOS activity, nitric oxide and cGMP but reduces activation of NOS induced by NMDA receptors activation. Hyperammonemia is responsible for both effects which will lead, independently, to alterations contributing to neurological alterations in hepatic encephalopathy.

A single transient episode of hyperammonemia induces long-lasting alterations in protein kinase A.

Hepatic encephalopathy in patients with liver disease is associated with poor prognosis. This could be due to the induction by the transient episode of hepatic encephalopathy of long-lasting alterations making patients more susceptible. We show that a single transient episode of hyperammonemia induces long-lasting alterations in signal transduction. The content of the regulatory subunit of the protein kinase dependent on cAMP (PKA-RI) is increased in erythrocytes from cirrhotic patients. This increase is reproduced in rats with portacaval anastomosis and in rats with hyperammonemia without liver failure, suggesting that hyperammonemia is responsible for increased PKA-RI in patients. We analyzed whether there is a correlation between ammonia levels and PKA-RI content in patients. All cirrhotic patients had increased content of PKA-RI. Some of them showed normal ammonia levels but had suffered previous hyperammonemia episodes. This suggested that a single transient episode of hyperammonemia could induce the long-lasting increase in PKA-RI. To assess this, we injected normal rats with ammonia and blood was taken at different times. Ammonia returned to basal levels at 2 h. However, PKA-RI was significantly increased in blood cells from rats injected with ammonia 3 wk after injection. In conclusion, it is shown that a single transient episode of hyperammonemia induces long-lasting alterations in signal transduction both in blood and brain. These alterations may contribute to the poor prognosis of patients suffering hepatic encephalopathy.

NMDA receptors in hyperammonemia and hepatic encephalopathy.

The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy.