NMDA Receptor antagonists prevent acute ammonia toxicity in mice

Hermenegildo, Carlos; Marcaida, Goizane; Montoliú, Carmina; Grisolı́a, Santiago; Miñana, María‐Dolores; Felipo, Vicente

doi:10.1007/bf02532401

Cited by 137 publications

(76 citation statements)

References 71 publications

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“…While considerable evidence documents that microglial activation contributes to the pathogenesis of AHE (as noted above), the reason for the absence of microglial activation in their study is not clear. However, these investigators used a relatively high concentration of ammonia ( pathophysiologically relevant as this concentration of ammonia induces acute deterioration of neurological function, development of myoclonic seizures and death within 5-10 min after ammonia injection, [65][66][67] thereby precluding the subsequent identification of microglial activation. The basis for such deterioration following treatment with high levels of ammonia is not known, but it suggests the possibility of some generalized negative systemic event(s) (e.g., in heart or lung) occurring as a consequence of the hyperammonemia.…”

Section: Inflammation In Hepatic Encephalopathymentioning

confidence: 99%

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

Jayakumar

Rao

Norenberg

2015

Journal of Clinical and Experimental Hepatology

102

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Hepatic encephalopathy (HE) is a major neurological complication of severe liver disease that presents in acute and chronic forms. While elevated brain ammonia level is known to be a major etiological factor in this disorder, recent studies have shown a significant role of neuroinflammation in the pathogenesis of both acute and chronic HE. This review summarizes the involvement of ammonia in the activation of microglia, as well as the means by which ammonia triggers inflammatory responses in these cells. Additionally, the role of ammonia in stimulating inflammatory events in brain endothelial cells (ECs), likely through the activation of the toll-like receptor-4 and the associated production of cytokines, as well as the stimulation of various inflammatory factors in ECs and in astrocytes, are discussed. This review also summarizes the inflammatory mechanisms by which activation of ECs and microglia impact on astrocytes leading to their dysfunction, ultimately contributing to astrocyte swelling/ brain edema in acute HE. The role of microglial activation and its contribution to the progression of neurobehavioral abnormalities in chronic HE are also briefly presented. We posit that a better understanding of the inflammatory events associated with acute and chronic HE will uncover novel therapeutic targets useful in the treatment of patients afflicted with HE. ( J CLIN EXP HEPATOL 2015;5:S21-S28) H epatic encephalopathy (HE) is the major neurological complication of severe liver disease. It presents in two forms, chronic HE and acute HE. Chronic HE (portal-systemic encephalopathy) usually occurs in patients with alcoholic liver cirrhosis and is characterized by impaired neurological function, including changes in personality, altered mood, diminished intellectual capacity, and abnormal muscle tone and tremor. 1 Acute HE (AHE, acute liver failure, ALF; fulminant hepatic failure) generally occurs following massive liver necrosis due to viral hepatitis (hepatitis B and C), hepatic neoplasms, vascular causes, or exposure to acetaminophen and other hepatotoxins. AHE is associated with the abrupt onset of delirium, seizures, and coma.The principal pathological change in chronic HE is characterized by Alzheimer type II astrocytosis, 2,3 which is characterized by astrocytes possessing enlarged, pale nuclei, often occurring in pairs, with the nuclei frequently displaying prominent nucleoli. Cerebral edema and associated increase in intracranial pressure leading to brain herniation are the characteristic features of AHE which occurs in upto 80% of patients with AHE 4-6 and represents the most frequent cause of death in these patients (70% mortality). 4,7 While the basis for the edema in AHE is poorly understood, astroglial swelling (cytotoxic edema) dominates the pathology in experimental animals, [8][9][10][11] as well as in humans. 12 Of interest, no significant or consistent morphologic changes have been identified in neurons or other neural cells. Such findings prompted the suggestion that HE fundamentally represents a pr...

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Section: Inflammation In Hepatic Encephalopathymentioning

confidence: 99%

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

Jayakumar

Rao

Norenberg

2015

Journal of Clinical and Experimental Hepatology

102

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“…Part of the cGMP formed is released into the extracellular space where it can be collected and served as a marker of NMDA-receptor-mediated NOS activity. This pathway is blocked by the pre-treatment of MK-801, a glutamate (NMDA) receptor antagonist (Hermenegildo et al, 1996(Hermenegildo et al, , 2000. Overactivation of NMDA receptors leading to an increase in NMDA/NOS/cGMP pathway has been shown to occur in acute hyperammonemia (Marcaida et al, 1992;Montoliu et al, 2002).…”

Section: Limited Concentrations Of Glutamine Synthetase Enzyme Substratementioning

confidence: 99%

Limited Capacity for Ammonia Removal by Brain in Chronic Liver Failure: Potential Role of Nitric Oxide

Rose

Felipo

2005

Metab Brain Dis

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. Limited capacity for ammonia removal by brain in chronic liver failure: potential role of nitric oxide. Metabolic brain disease, 20(4), p. ABSTRACTChronic liver failure leads to hyperammonemia and consequently increased brain ammonia concentrations, resulting in hepatic encephalopathy. When the liver fails to regulate ammonia concentrations, the brain, devoid of a urea cycle, relies solely on the amidation of glutamate to glutamine through glutamine synthetase, to efficiently clear ammonia. Surprisingly, under hyperammonemic conditions, the brain is not capable of increasing its capacity to remove ammonia, which even decreases in some regions of the brain. This non-induction of glutamine synthetase in astrocytes could result from possible limiting substrates or cofactors for the enzyme, or an indirect effect of ammonia on glutamine synthetase expression. In addition, there is evidence that nitration of the enzyme resulting from exposure to nitric oxide could also be implicated. The present review summarizes these possible factors involved in limiting the increase in capacity of glutamine synthetase in brain, in chronic liver failure.

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“…During aestivation, ammonia excretion would be impeded, leading to its accumulation in the body. Since ammonia is toxic (Cooper and Plum 1987;Hermenegildo et al 1996;Ip et al 2001;Brusilow 2002;Felipo and Butterworth 2002;Rose 2002), African lungWshes have to avoid ammonia toxicity during aestivation, and they achieve this through an increase in urea synthesis (Smith 1930(Smith , 1935Janssens 1964;Janssens and Cohen 1968a, b) and a suppression of N production as ammonia (see Ip et al 2004;Chew et al 2006 for reviews). Recently, Chew et al (2004) demonstrated that the rate of urea synthesis increased 2.4-to 3.8-fold and the rate of N production decreased by 72% in P. dolloi during 40 days of aestivation in air (normoxia) when compared with the immersed control.…”

mentioning

confidence: 99%

Effects of hypoxia on the energy status and nitrogen metabolism of African lungfish during aestivation in a mucus cocoon

et al. 2008

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We examined the energy status, nitrogen metabolism and hepatic glutamate dehydrogenase activity in the African lungWsh Protopterus annectens during aestivation in normoxia (air) or hypoxia (2% O 2 in N 2 ), with tissues sampled on day 3 (aerial exposure with preparation for aestivation), day 6 (entering into aestivation) or day 12 (undergoing aestivation). There was no accumulation of ammonia in tissues of Wsh exposed to normoxia or hypoxia throughout the 12-day period. Ammonia toxicity was avoided by increased urea synthesis and/or decreased endogenous N production (as ammonia), but the dependency on these two mechanisms diVered between the normoxic and the hypoxic Wsh. The rate of urea synthesis increased 2.4-fold, with only a 12% decrease in the rate of N production in the normoxic Wsh. By contrast, the rate of N production in the hypoxic Wsh decreased by 58%, with no increase in the rate of urea synthesis. Using in vivo 31 P NMR spectroscopy, it was demonstrated that hypoxia led to signiWcantly lower ATP concentration on day 12 and signiWcantly lower creatine phosphate concentration on days 1, 6, 9 and 12 in the anterior region of the Wsh as compared with normoxia. Additionally, the hypoxic Wsh had lower creatine phosphate concentration in the middle region than the normoxic Wsh on day 9. Hence, lowering the dependency on increased urea synthesis to detoxify ammonia, which is energy intensive by reducing N production, would conserve cellular energy during aestivation in hypoxia. Indeed, there were signiWcant increases in glutamate concentrations in tissues of Wsh aestivating in hypoxia, which indicates decreases in its degradation and/or transamination. Furthermore, there were signiWcant increases in the hepatic glutamate dehydrogenase (GDH) amination activity, the amination/deamination ratio and the dependency of the amination activity on ADP activation in Wsh on days 6 and 12 in hypoxia, but similar changes occurred only in the normoxic Wsh on day 12. Therefore, our results indicate for the Wrst time that P. annectens exhibited diVerent adaptive responses during aestivation in normoxia and in hypoxia. They also indicate that reduction in nitrogen metabolism, and probably metabolic rate, did not occur simply in association with aestivation (in normoxia) but responded more eVectively to a combined eVect of aestivation and hypoxia.

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NMDA Receptor antagonists prevent acute ammonia toxicity in mice

Cited by 137 publications

References 71 publications

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

Limited Capacity for Ammonia Removal by Brain in Chronic Liver Failure: Potential Role of Nitric Oxide

Effects of hypoxia on the energy status and nitrogen metabolism of African lungfish during aestivation in a mucus cocoon

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