Table 1.

Evidence of biochemical changes-induced by HE.

Encephalopathy	Experimental model	Evidence	Author
HE	Pigs	It has been shown the association between extracellular brain ammonia and intracranial pressure (ICP), suggesting that ICP could serve as marker for HE.	[71]
HE	Rats administered locally with fluoroacetate in the hippocampus by microdialysis	Ammonia alters the function of astrocytes, facilitating its entry into the brain. This physiological fact contributes to the development of HE.	[72]
HE	Portacaval shunt (PCS)	Quinolinic acid (QUIN) and l-tryptophan (l-TRP) are not involved in HE. Elevated l-TRP availability increased the QUIN levels to a similar degree in both sham and PCS rats.	[73]
HE	Rats with ischemic liver failure	The significant three-fold increase of extracellular glycine measured by in vivo cerebral microdialysis suggests the participation of NMDA.	[74]
HE	Rats administered with galactosamine	The blockage of NMDA receptors by continuous administration of MK-801 or memantine induces protection against acute liver failure. The blockage of NMDA receptors increases the survival rate from 23% to 62% in rats.	[75]
HE	Rats with hyperammonemia induced by intracerebral ammonia infusion	The marked elevation in glutamate levels suggests that high ammonia levels may increase the excitability of the brain and this condition may serve as a key in the onset of HE.	[76]
HE	Rats with liver failure induced by thioacetamide	Experimental data show a significant increase in extracellular hippocampal glutamate concentration.	[77]
HE	Rats with hypothermia	Beneficial effect of hypothermia in rats with hepatic devascularization that induces ALF is mediated via mechanisms involving reduced blood-brain transfer of ammonia and/or reduction of extracellular brain glutamate concentrations.	[78]
HE	PCS and Sham rats	Participation of glutamate-nitric oxide-cyclic guanosine monophosphate (cGMP) was shown. The basal NOS activity, nitrites and cGMP are increased in cortex of rats with hyperammonemia or liver failure. These are associated to increased inducible NOS expression. It was found; in both animal models and in neurons exposed to ammonia, an impaired NOS activation by NMDA.	[79]
HE	Hyperammonemic rats	It was found increased tonic activation of NMDA receptors leading to reduced activity of nNOS and of the glutamate-NO-cGMP pathway.	[80]
HE	Rats with ALF	Amino acids play a role in the pathogenesis of hepatic encephalopathy in ALF. They found that extracellular concentration of the neuroactive amino acids glutamate, taurine and glycine were increased, whereas extracellular concentration of aspartate and GABA were unaltered and that glutamine of decreased.	[81]
HE	Rats with subclinical hepatic encephalopathy induced by intraperitoneal thioacetamide	In cerebral cortical microdialysates of rats was found that dialysate concentration of the neuroactive amino acids taurine (Tau), glutamate (Glu) and aspartate (Asp) were 30% to 50% higher than that found in control.	[82]
HE	Rats with HE induced by ALF	The precursors of monoamines, as well as monoamines and their metabolites, altered neuronal excitability and contribute to the characteristics of HE extracellular brain concentrations of aromatic amino acids (AAAs) and of valine and leucine (precursors of monoamine neurotransmitters) were elevated 2 to 4-fold following hepatic devascularization and these increases were significantly correlated to arterial ammonia concentration.	[83,84]
HE	Animals administered with flumazenil	Extracellular concentration of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, decreased to 39% compared with sham-operated animals, without changes in the dopamine level. The treatment with flumazenil completely abolished the decrease in the metabolite. Although in this study the glutamate level in the injured animals decreased to 42% of that in sham-operated animals, there are not increases in the glutamate levels in animals treated with flumazenil. In conclusion, the restoration of the central dopaminergic function could be a relevant factor in the improvement of HE.	[85]
HE	Hyperammonemics rats	The locomotion induced by injection of the mGluR agonist dihydroxyphenylglycine (DHPG) into nucleus accumbens was increased. Also in control rats DHPG increased extracellular dopamine (400%), but glutamate was unchanged. Whereas that in hyperammonemic rats DHPG increased extracellular glutamate (600%), effect prevent by blocking mGluR1 receptor. This result suggests that modulation of locomotor and neurochemical functions by mGluRs in nucleus accumbens are strongly altered in hyperammonemia.	[86]
HE	Rats with acute HE induced thioacetamide administration	The impairment of modulation of striatal DA discharge and metabolism by glutamate, acting at NMDA receptors, contributes to the motor disturbances in HE.	[87]
HE	Rats with liver failure due to PCS	The activation of the normal neuronal circuit in VP, SNr, MDT, and VMT was determined using in vivo brain microdialysis. It is suggested that DHPG-induced increase in dopamine would activate the normal neuronal circuit, while an increase in glutamate would activate the alternative circuit.	[88]
HE	Model of chronic HE, by acute comainducing by ammonium acetate (5.2 mmol/kg, i.p.)	The serotonergic system is also affected in the HE. The extracellular levels of 5-hydroxytryptamine (5-HT) is unaltered and that of its major metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), is increased in the frontal neocortical of PCS rats. Results suggest that the increase brain ammonia may increase neuronal 5-HT release in HE, which in turn could be involved in the severe stages of HE.	[89]
HE	Rats with thioacetamide (TAA)-induced HE	Serotonergic neurotransmission is altered in the frontal cortex of rats with thioacetamide (TAA)-induced HE. Where found that 5-HIAA and high K+-evoked 5-HT release were increased.	[90]
HE	Rats with acute liver failure	Noradrenergic system is affected and the central noradrenergic mechanisms may contribute to the central nervous system manifestations of HE. They showed that the increase of extracellular brain concentrations of the noradrenaline (NA) from frontal cortex and thalamus is associated to loss of NA transporter sites and depletion of central NA stores.	[91]
HE	Rats where the administration of ammonium chloride (ammonia)	Extracellar glutathione (GSH) is involved in the ammonia toxicity present in HE microdialysis probe to the rat prefrontal cortex increased GSH. This increase is abrogated by fluoroacetate, an inhibitor of astrocytic energy metabolism, and by buthionine sulfoximine, an inhibitor of glutathione synthesis. Their results suggest that in rats with hiperammonemia promote GSH synthesis and this may improve the availability of precursors for GSH synthesis in neurons and their resistance to ammonia toxicity present in HE.	[92]
Fulminant hepatic encephalopathy	Intracerebral microdialysis during cardiac resuscitation in rats	They measured the chemical markers of energy metabolism glucose, lactate, pyruvate, and the marker of cell membrane damage glycerol and found that all markers with exception for subcutaneous glucose, showed a sudden and significant increase during resuscitation and a prolonged period afterwards and finally after some hours all values returned to normal.	[93]
Portal-systemic encephalopathy	PCS rats	They evaluated the participation of serotonin system in PCS, and found an increased brain tissue and extracellular concentrations of serotonin in neocortical region of the rats with this encephalopathy.	[89]