Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by intestinal blood in rats with portacaval anastomosis

Oria, Marc; Romero-Giménez, Jordi; Arranz, José Antonio; Riudor, E.; Raguer, Nuria; Córdoba, Juan

doi:10.1016/j.jhep.2011.06.026

Cited by 21 publications

(21 citation statements)

References 37 publications

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“…Previous studies have consistently shown that the administration of ornithine and phenylacetate results in a reduction in ammonia levels and an increase in urinary phenylacetylglutamine (7,20,31). However, in each study, the reduction in ammonia did not stoichiometrically correlate with an increase in urinary phenylacetylglutamine.…”

Section: Discussionmentioning

confidence: 60%

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L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway

Kristiansen

Rose

Fuskevåg

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Glycine is an important ammoniagenic amino acid, which is increased in acute liver failure (ALF). We have previously shown that L-ornithine phenylacetate (OP) attenuates ammonia rise and intracranial pressure in pigs suffering from ALF but failed to demonstrate a stoichiometric relationship between change in plasma ammonia levels and excretion of phenylacetylglutamine in urine. The aim was to investigate the impact of OP treatment on the phenylacetylglycine pathway as an alternative and additional ammonia-lowering pathway. A well-validated and -characterized large porcine model of ALF (portacaval anastomosis, followed by hepatic artery ligation), which recapitulates the cardinal features of human ALF, was used. Twenty-four female pigs were randomized into three groups: (1) sham operated + vehicle, (2) ALF + vehicle, and (3) ALF + OP. There was a significant increase in arterial glycine concentration in ALF (P < 0.001 compared with sham), with a three-fold increase in glycine release into the systemic circulation from the kidney compared with the sham group. This increase was attenuated in both the blood and brain of the OP-treated animals (P < 0.001 and P < 0.05, respectively), and the attenuation was associated with renal removal of glycine through excretion of the conjugation product phenylacetylglycine in urine (ALF + vehicle: 1,060 ± 106 μmol/l; ALF + OP: 27,625 ± 2,670 μmol/l; P < 0.003). Data from this study provide solid evidence for the existence of a novel, additional pathway for ammonia removal in ALF, involving glycine production and removal, which is targeted by OP.

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Section: Discussionmentioning

confidence: 60%

“…Similar beneficial effects of OP were also demonstrated in cirrhotic (7) and portacaval-shunted rats given a simulated GI-bleed (20). The mechanism by which OP lowers ammonia is hypothesized to be through the provision of glutamate through transamination of L-ornithine in skeletal muscle.…”

mentioning

confidence: 63%

L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway

Kristiansen

Rose

Fuskevåg

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…An increase in extracellular glutamate has been documented to be associated with severe HE (Michalak et al, 1996, Oria et al, 2012, Rose et al, 2007and Tofteng et al, 2002, and has been described to occur as a result of decreased mRNA and protein expression of astrocytic glutamate transporters (Desjardins et al, 2001, Knecht et al, 1997, Norenberg et al, 1997and Suárez et al, 2000. Subsequently, this is accompanied by a decrease in GS activity, but the continuous presence of high glutamine levels (Desjardins et al, 1999 andRao et al, 2005).…”

Section: Glutamine/glutamatementioning

confidence: 99%

“…Therefore, it is possible, as a defense mechanism, that upon swelling of the astrocyte (ammonia-induced glutamate uptake and glutamine formation/accumulation), the astrocyte shuts down (downregulates) the transport of glutamate into the cell to avoid further intracellular hypertonicity and cell swelling. This in turn, will consequently lead to an increase in extracellular glutamate causing hyperexcitability and contributing to severe HE (Oria et al, 2012 andRose et al, 2007) (Fig. 4B).…”

Section: Glutamine/glutamatementioning

confidence: 99%

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Bosoi

Rose

2013

Neurochemistry International

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Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed. HighlightsBrain edema is a common feature in ALF and CLD. HE is inconsistently associated with the presence of brain edema. Fibrous and protoplasmic astrocytes are differentially implicated in the pathogenesis of HE. The pathogenesis of HE is multifactorial causing an array of neurological symptoms.

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“…Phenylacetate conjugates with the newly formed glutamine to form phenylacetylglutamine which cannot be metabolized by glutaminase and thus prevents an ammonia rebound effect (Jalan et al 2007). OP has consistently been shown to decrease arterial ammonia levels both in humans and in several animal models of both acute and chronic liver failure (Ytrebo et al 2009;Davies et al 2009;Balasubramaniyan et al 2012;Oria et al 2012;Wright et al 2012;Dadsetan et al 2013;Ventura-Cots et al 2013;JoverCobos et al 2014). We have previously shown a significant reduction in arterial ammonia by OP treatment in a porcine model of ALF (Ytrebo et al 2009).…”

Section: Glycine and The Nmda-receptormentioning

confidence: 99%

Glycine and hyperammonemia: potential target for the treatment of hepatic encephalopathy

2016

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Hepatic encephalopathy (HE) is a neuropsychiatric disorder caused by hepatic dysfunction. Numerous studies dictate that ammonia plays an important role in the pathogenesis of HE, and hyperammonemia can lead to alterations in amino acid homeostasis. Glutamine and glycine are both ammoniagenic amino acids that are increased in liver failure. Modulating the levels of glutamine and glycine has shown to reduce ammonia concentration in hyperammonemia. Ornithine Phenylacetate (OP) has consistently been shown to reduce arterial ammonia levels in liver failure by modulating glutamine levels. In addition to this, OP has also been found to modulate glycine concentration providing an additional ammonia removing effect. Data support that glycine also serves an important role in N-methyl D-aspartate (NMDA) receptor mediated neurotransmission in HE. This potential important role for glycine in the pathogenesis of HE merits further investigations.

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Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by intestinal blood in rats with portacaval anastomosis

Cited by 21 publications

References 37 publications

L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway

L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Glycine and hyperammonemia: potential target for the treatment of hepatic encephalopathy

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