Hyperammonemia, brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paracetamol intoxication

Scorticati, Camila; Prestifilippo, Juan Pablo; Eizayaga, Francisco Xavier; Castro, Juan Luis; Romay, Salvador; Fernández, María Alejandra; Lemberg, A; Perazzo, Juan Carlos

doi:10.3748/wjg.v10.i9.1321

Cited by 33 publications

(27 citation statements)

References 19 publications

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“…In previous experiments with this rat model, alterations in the CNS have been documented, including BBB permeability modifications [5,20] . The impact of PH on the BBB has been demonstrated in rats, in which, 40 d after portal vein stricture, the BBB recovers its function associated to normalize portal pressure and the impermeability to dyes [20] .…”

Section: Discussionmentioning

confidence: 80%

“…HE in acute and chronic liver disease is a complex syndrome, associated frequently with hyperammonemia. Increases in blood brain barrier (BBB) permeability present in PH, allow ammonia ions and other neurotoxic substances to penetrate brain tissue [3][4][5][6] . Hyperammonemia is caused by a defect in the liver parenchyma that forms urea from intestinal nitrogenic substances, and vein shunts from the splanchnic circulation carry it into the general circulation [7] .…”

Section: Introductionmentioning

confidence: 99%

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Glutamine synthetase activity and glutamate uptake in hippocampus and frontal cortex in portal hypertensive rats

Acosta¹,

Fernández²,

Roselló³

et al. 2009

WJG

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AIM:To study glutamine synthetase (GS) activity and glutamate uptake in the hippocampus and frontal cortex (FC) from rats with prehepatic portal vein hypertension. METHODS:Male Wistar rats were divided into shamoperated group and a portal hypertension (PH) group with a regulated stricture of the portal vein. Animals were sacrificed by decapitation 14 d after portal vein stricture. GS activity was determined in the hippocampus and FC. Specific uptake of radiolabeled L-glutamate was studied using synaptosome-enriched fractions that were freshly prepared from both brain areas. RESULTS:We observed that the activity of GS increased in the hippocampus of PH rats, as compared to control animals, and decreased in the FC. A significant decrease in glutamate uptake was found in both brain areas, and was more marked in the hippocampus. The decrease in glutamate uptake might have been caused by a deficient transport function, significantly and persistent increase in this excitatory neurotransmitter activity. CONCLUSION:The presence of moderate ammonia blood levels may add to the toxicity of excitotoxic glutamate in the brain, which causes alterations in brain function. Portal vein stricture that causes portal hypertension modifies the normal function in some brain regions.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Glutamine synthetase activity and glutamate uptake in hippocampus and frontal cortex in portal hypertensive rats

Acosta¹,

Fernández²,

Roselló³

et al. 2009

WJG

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“…As we previously described, high ammonia blood concentrations exist in prehepatic PH rats [5][6][7] . Because of that, and in order to maintain the hyperammonemic milieu, 100 M ammonium acetate was added to both, the preincubation and incubation media, only to the APs from PH rats.…”

Section: Ex Vivo Studiesmentioning

confidence: 99%

“…Several substances have been proposed as mediators of this hypodynamic circulatory state including glucagon, prostacyclins and endotoxin, especially nitric oxide (NO) [2][3][4] . Furthermore, we have demonstrated that PH rats are a subclinic model of PSHE, since rats with PH have hyperammonemia, electrophysiology alterations, blood-brain barrier breakdown, astrocyte alterations; changes in catecholamine uptake and hippocampal mitochondrial dysfunction [5][6][7][8][9] . In addition, the relationship between hyperammonemic syndromes and enhanced NO production by increased neuronal NO synthase (nNOS, a NOS enzyme isoform) protein expression in different brain regions is well known [10,11] .…”

Section: Introductionmentioning

confidence: 99%

Role of Ammonia and Nitric Oxide in the Decrease in Plasma Prolactin Levels in Prehepatic Portal Hypertensive Male Rats

Scorticati

Perazzo²,

Rettori

et al. 2006

Neuroimmunomodulation

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Objectives: Since very little is known about neuroendocrine changes that occur in portal-systemic hepatic encephalopathy, we studied plasma prolactin (PRL) levels and the involvement of hyperammonemia, nitric oxide (NO) and dopaminergic and adrenergic systems in the control of this hormone secretion in a male rat model of prehepatic portal hypertension (PH). Methods: We conducted in vivo studies to determine plasma ammonia and PRL levels. Dopamine (DA), dihydroxyphenylacetic acid (DOPAC), epinephrine and norepinephrine content in medial basal hypothalamus (MBH) and anterior pituitary (AP) were measured. In addition, NO synthase (NOS) activity and protein expression were evaluated in APs. In in vitro studies, the APs from intact rats were incubated with different doses of ammonia and PRL secretion was determined. In ex vivo studies, the APs from normal and PH rats were incubated in the presence of ammonia and/or a NOS inhibitor, N^G-nitro-L-arginine-methyl ester (L-NAME) and PRL secretion was determined. Results: PH rats had a significant increase in plasma ammonia levels (p < 0.001) and a decrease in plasma PRL levels (p < 0.05). Neither DA nor DOPAC content or DOPAC/DA ratios were modified in both MBH and APs; however, we observed a significant increase in norepinephrine content in both MBH and AP (p < 0.001 and p < 0.05, respectively) and a significant increase in epinephrine in APs (p < 0.001). Moreover, PH produced an increase in NOS activity (p < 0.01) and NOS protein expression (p < 0.0001) in APs. The ammonia (100 µM) significantly reduced PRL secretion from APs in vitro (p < 0.05). The presence of L-NAME, an inhibitor of NOS, abrogated the inhibitory effect of ammonia on PRL secretion from APs from control and PH rats. Conclusions: We found that plasma PRL levels were decreased in PH rats probably due to the high ammonia levels. The central noradrenergic system could also mediate this decrease. Also, the increase in NOS activity and/or content in AP induced NO production that directly inhibited PRL secretion from the AP, without the participation of the dopaminergic system.

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“…Our laboratory has shown [94] that the altered integrity of BBB gets back to normal in a HE��PVL induced model after portal pressure returns to a normal value. Moreover, in a group of animals with por�� tal hypertension (PVL��induced) plus acetaminophen, be�� havioral changes and increased the BBB alterations were observed [95] . Therefore it can be concluded that the BBB is an area where further research is needed to integrate all components and generate a view of the totality in HE.…”

Section: Blood Brain Barrier Brain Barrier Brain Barriermentioning

confidence: 99%

Hepatic encephalopathy: An approach to its multiple pathophysiological features

Perazzo¹,

Tallis²,

Delfante³

et al. 2012

WJH

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Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two-to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly ex-HE is rapidly ex-HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics.

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Hyperammonemia, brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paracetamol intoxication

Cited by 33 publications

References 19 publications

Glutamine synthetase activity and glutamate uptake in hippocampus and frontal cortex in portal hypertensive rats

Glutamine synthetase activity and glutamate uptake in hippocampus and frontal cortex in portal hypertensive rats

Role of Ammonia and Nitric Oxide in the Decrease in Plasma Prolactin Levels in Prehepatic Portal Hypertensive Male Rats

Hepatic encephalopathy: An approach to its multiple pathophysiological features

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