Glutamate‐induced activation of nitric oxide synthase is impaired in cerebral cortex<i>in vivo</i>in rats with chronic liver failure

Rodrigo, Regina; Erceg, Slaven; Rodrı́guez-Dı́az, Jesús; Sáez‐Valero, Javier; Piedrafita, Blanca; Suárez, I.; Felipo, Vicente

doi:10.1111/j.1471-4159.2006.04446.x

Cited by 37 publications

(23 citation statements)

References 49 publications

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“…3 We therefore tested whether ibuprofen-induced restoration of learning is associated with restoration of the function of the pathway in cerebral cortex in vivo (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…In cerebral cortex of PCS rats, the impairment of the pathway is mainly due to impaired activation of neuronal NOS (nNOS). 3 It is not yet clear which is the mechanisms by which portacaval shunt results in reduced activation of nNOS following activation of NMDA receptors, and it is therefore difficult to discuss how ibuprofen may normalize this activation. The mechanisms by which chronic liver failure affects modulation of nNOS activity by calcium may include alterations in phosphorylation or in the content or function of the proteins that modulate nNOS localization.…”

Section: Discussionmentioning

confidence: 99%

“…Inducible NO synthase (iNOS) activity was determined as the activity of NOS that is calciumindependent. Calcium-independent NOS activity was measured by the conversion of [ 14 C]arginine to [ 14 C]citrulline as described in Rodrigo et al 3 Briefly, rats were killed by decapitation and cerebral cortex was homogenized in 5 volumes of ice-cold buffer A (20 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, 0.32 M sucrose, 1 mM dithiothreitol, 10 mg/l leupeptin, 10 mg/l pepstatin A, and 1 mM ethylene glycol tetraacetic acid to chelate endogenous calcium; pH 7.4). Homogenates (25 l) were incubated for 60 minutes at 37°C with 100 l of reaction mixture containing 200 M reduced nicotinamide adenine dinucleotide phosphate, 100 M tetrahydro-biopterin, 2 mM EDTA, 1.2 mM ethylene glycol tetraacetic acid and 1 Ci/ml L-[ 14 C]arginine monohydrochloride in buffer A and 75 l distilled water.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

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Inflammation and hepatic encephalopathy

et al. 2007

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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

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“…3 We therefore tested whether ibuprofen-induced restoration of learning is associated with restoration of the function of the pathway in cerebral cortex in vivo (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Inflammation and hepatic encephalopathy

et al. 2007

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“…The glutamate content in the microdialysis samples and the content of glutamate, glutamine, aspartate, alanine, phenylalanine, tyrosine, tryptophan, isoleucine, leucine, and valine in serum were analyzed by HPLC using a Waters reverse-phase HPLC system with fluorescence detection and precolumn o-phthalaldehyde derivatization (Waters, Milford, MA) as previously described (28). It is well known that in liver failure aromatic amino acids increase and branched chain amino acids decrease.…”

Section: Methodsmentioning

confidence: 99%

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

Cauli¹,

Rodrigo²,

Boix³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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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. hyperammonemia; hepatic encephalopathy; galactosamine; MK-801 ACUTE LIVER FAILURE (ALF) may lead to massive liver cell death and severe liver dysfunction. As a consequence, hepatic encephalopathy and multiorgan failure develop rapidly and may lead to rapid death of patients unless they receive a liver transplantation. However, the number of livers available for transplantation is low, leading to long waiting times for transplantation and to death of a relevant percentage of patients before a liver suitable for transplantation becomes available.The liver has a high capacity for regeneration that may allow complete recovery even in patients who have severe liver injury and liver mass loss. It would be therefore of great clinical interest to have procedures to delay ALF-induced death. This would increase survival of patients with ALF either by allowing enough time for regeneration of the liver by itself or to receive a suitable liver for transplantation.The mechanisms by which ALF leads to death are not well understood. The primary event is the death of liver cells by necrosis and apoptosis. This leads to inflammatory responses and decreased functionality of the liver, resulting in decreased elimination of toxic substances, including ammonia, and decreased synthesis and release of substances such as albumin, etc. Progression of ALF leads to multiorgan failure, systemic inflammatory response, hepatic encephalopathy, cerebral edema, and increased intracranial pressure, which seem to be the most important immediate causes of mortality in patients with ALF. Preventing or delaying these processes may help to delay ALF-induced death. One of t...

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Elevated glutamate and NMDA disrupt production of the second messenger cyclic GMP in the early postnatal mouse cortex

Currie¹,

Corlew²,

Vente³

et al. 2009

Developmental Neurobiology

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The second messenger cyclic guanosine monophosphate (cGMP) plays many roles during nervous system development. Consequently, cGMP production shows complex patterns of regulation throughout early development. Elevated glutamate levels are known to increase cGMP levels in the mature nervous system. A number of clinical conditions including ischemia and perinatal asphyxia can result in elevated glutamate levels in the developing brain. To investigate the effects of elevated glutamate levels on cGMP in the developing cortex we exposed mouse brain slices to glutamate or N-methyl D-aspartate (NMDA). We find that at early postnatal stages when the endogenous production of cGMP is high, glutamate or NMDA exposure results in a significant lowering of the overall production of cGMP in the cortex, unlike the situation in the mature brain. However, this response pattern is complex with regional and cell-type specific exceptions to the overall lowered cGMP production. These data emphasize that the response of the developing brain to physiological disturbances can be different from that of the mature brain, and must be considered in the context of the developmental events occurring at the time of disturbance.

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Glutamate‐induced activation of nitric oxide synthase is impaired in cerebral cortexin vivoin rats with chronic liver failure

Cited by 37 publications

References 49 publications

Inflammation and hepatic encephalopathy

Inflammation and hepatic encephalopathy

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

Elevated glutamate and NMDA disrupt production of the second messenger cyclic GMP in the early postnatal mouse cortex

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