Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress

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Simplified representation of the six-glutamate release mechanism: aswelling-induced opening of volumeregulated anion channels [VRAC]; bCa2+-dependent exocytosis; creverse operation of excitatory amino acid transporters [EAAT]; d-the cystine-glutamate exchanger; e-connexin hemichannels and f-the P2X7 receptor." ] ] ] "textoCompleto" => "AbbreviationsHE: hepatic encephalopathyCNS: central nervous systemiNOS: inducible nitric oxide synthaseROS: reactive oxygen speciesBBB: blood brain barrierMSO: methionine-sulfoximineMPT: mitochondrial permeability transitionGS: glutamine synthetaseOS: oxidative stressIntroductionHepatic encephalopathy (HE) with subclinical and clinical symptoms constitutes a serious complication in the evolution of acute and chronic hepatic failure. The precise pathophysiological mechanism responsible for HE is not completely understood, and sequential events, cascades and pathways must be clarified before a complete answer is obtained.Alterations in normal brain function following hepatic injury represent a wide spectrum of psychoneurological symptoms that range from somnolence and excitation to confusion and coma, and are usually caused by brain edema, intracranial hypertension and changes in the function and morphology of brain cells.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>In the early years of the twentieth century, the Russian physiologist Ivan Pavlov described the association of the Eck’s fistula (portacaval anastomosis in dogs) with the presence of ammonia, which shunted into the blood from the intestine,(Blendis, 2006).<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The pathogenic role of portosystemic shunts and elevated blood ammonia concentrations are part of the hepatic encephalopathy syndrome.Hepatic encephalopathy, as present in fulminant liver failure, appears in acute form, with rapid evolution to coma, seizures, and a high mortality rate. It usually follows cerebral herniation due to intracranial hypertension and hypoxia. A second form of HE presents a slower onset and milder symptoms and can be reversible. A third form of HE presents a chronic evolution with a prolonged persistence of neuropsychiatry symptoms.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Another form, a subclinical HE or mild encephalopathy with superficial neuropsychiatric symptoms, which must be recognized to avoid further progression, has also been described.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Acute and chronic liver failure are associated with many biochemical abnormalities in plasma and brain tissue, which partially explains why the presence of abnormal substances correlate well with the occurrence of memory and behavioral impairments, as observed even with moderate ammonia blood levels in HE.Among these substances, different concentrations of ammonia, amino acids and neurotransmitters as serotonin, glutamate, glutamine and intermediary metabolites (lactate and pyruvate) can be found.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>In normal subjects, intestinal ammonia, produced from nitrogen products, is taken up by the liver and metabolized to urea. Damaged livers do not accomplish this step adequately, and pathologies as cirrhosis and portal vein thrombosis do not allow splanchnic blood flow to penetrate into the parenchyma; then, portosystemic shunts are created and ammonia and other metabolites are sent to the systemic circulation and finally reach the brain.In congenital urea cycle disorders, as seen in children with inborn errors of urea cycle enzymes, blood ammonia levels rise soon after birth.In the hepatic acinus, urea and glutamine metabolism are heterogeneously distributed, being urea synthesis and the enzyme glutaminase periportally localized and glutamine synthetase perivenously localized. Then, the periportal region has a low affinity but a high capacity for ammonia detoxification. Liver glutamine synthetase acts as a scavenger agent for ammonia, and when liver insuffiency is present, a diminished scavenger capacity takes place.Brain tissue does not have an effective urea cycle, and then the glutamine synthetase from astrocytes is in charge of ammonia and other toxic substances detoxification, as well.The key role of ammoniaSome years ago, we observed that not always blood ammonia levels correlate with the degree of psychoneurological symptoms in liver cirrhosis. As a result of these observations we decided to use the brain isoenzyme of creatinine kinase as an approximate marker of brain impairment.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Our results indicated a good relationship between liver failure and the blood concentration of this isoenzyme.Abou-Assi et al.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> reported that, in some cases, there is a lack of correlation between blood ammonia levels and stages of HE, presuming that there are other factors that participate in HE pathophysiology.Forty per cent of ammonia is generated by the intestine from nitrogenate substances, caused by the action of bacterial urease and amino acid oxidases, and the other 60% is derived from the metabolism of glutamine and the transamination of other amino acids.Normally, the efficiency by which liver removes intestinal ammonia maintains it at a low blood concentration. Besides, ammonia is generated as a metabolite product in other cells, especially in muscles. It must be recalled that muscles may remove ammonia ions from blood, changing its plasma concentration. The reactions that are catalyzed by the enzyme glutamate dehydrogenase, glutaminase and AMP-deaminase generate important amounts of ammonia.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Ammonia either enters the brain by diffusion from the blood or cerebrospinal fluid or is formed in situ from the metabolism of endogenous nitrogen-containing substances. Its excess is toxic to the central nervous system (CNS). As the brain does not produce urea from ammonia, its removal relies almost exclusively on glutamine synthetase, basically localized in astrocytes.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>It has been demonstrated in several studies that ammonia ions participate actively in neuron-astrocyte metabolic interaction, specifically in the functioning of the glutamate/glutamine cycle.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>The morphopathological findings in HE and other hyperammonemic conditions are localized in astrocytes rather than in neurons. The Alzheimer type II astrocyte change is the distinctive morphological alteration in brain of cirrhotic astrocytes, hyperammonemic congenical pathologies and urea cycle disorders.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>The experimental findings by Cummins et al. are, to a certain extent, similar to our results obtained with our model of encephalopathy and prehepatic portal hypertension, with low ammonia concentration and brain damage.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Ammonia toxic effects act inhibiting the tricarboxylic acid cycle enzymes, •-ketoglutarate dehydrogenase (in vitro)<a class="elsevierStyleCrossRef" href="#bib0050">10</a> and stimulate phospho-fructokinase and other glycolytic enzymes in brain tissue.Ammonia inhibits excitatory post-synaptic potentials, thereby, producing a general depression of the CNS function; and high levels produce brain energy failure due to its inhibitory action on key tricarboxylic acid cycle enzymes.The metabolism of ammonia to glutamine appears to be necessary, and is followed by an osmotic disturbance in the brain, mitochondrial dysfunction with oxidative stress, and alterations in brain glucose metabolism. Cerebral blood flow is also altered and strongly influences the development of brain edema and intracranial hypertension. Added factors, such as systemic inflammation, alterations in the brain extracellular concentration of amino acids and neurotransmitters, may contribute to the cerebral alterations in acute liver failure.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>Elevated brain ammonia level is an important etiologic factor in astrocyte swelling and brain edema, the main neuropathological findings in the acute form of hepatic encephalopathy. One factor known to be activated by oxidative/nitrosative stress and mitogen-activated protein kinases (both considered important elements in astrocyte swelling) is nuclear factor kappaB a transcription factor that activates the inducible nitric oxide synthase (iNOS) and other genes. Nitric oxide, the product of iNOS, is known to cause astrocyte swelling.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>Görg et al. identified the cerebral RNA oxidation as a not yet recognized consequence of acute ammonia intoxication. RNA oxidation may affect gene expression and local protein synthesis, and may thereby provide another link between reactive oxygen species/reactive nitrogen oxide species production, and ammonia toxicity. Also, oxidized RNA species may participate in post-synaptic protein synthesis, which is normally a biochemical substrate for learning and memory consolidation.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>Bai et al.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> have proposed that ammonia induces the mitochondrial permeability transition in cultured astrocytes, which may be a factor in the mitochondrial dysfunction associated with HE and other hyperammonemic states (see below).Glutamate metabolism alterationGlutamate is the main excitatory neurotransmitter in the mammalian CNS. Glutamate modulates several brain processes, including the encoding of information, the formation and retrieval of memories, spatial recognition and the maintenance of consciousness.Glutamatergic neurotransmission involves several steps, beginning with the release of glutamate from the pre-synaptic neuron; its presence in the extracellular space activates glutamate receptors present in the synaptic membranes, leading to activation of signal transduction pathways related to these receptors. Glutamate is removed from the synaptic cleft by specific glutamate transporters located mainly in astrocytes, avoiding overstimulation of glutamate receptors. The alterations in any of these steps may result in impairment of glutamatergic neurotransmission, leading to neurological alterations, especially those seen in neurodegenerative disease. In addition, the increased excitotoxicity of glutamate produces brain damage, as it also occurs in brain ischemia, anoxia and trauma.Astrocytic glutamate transportersThere is increasing evidence implying that HE in acute liver failure is the result of altered glutamatergic function. Brain glutamate metabolism constitutes its synthesis, uptake and release, and depends on the last two steps on the normal transporter function; then again, toxic substances and abnormal detoxification mechanisms are responsible for HE syndrome.Schmidt et al. studied hippocampal slices exposed to serum and cerebrospinal fluid obtained from patients with chronic liver disease who had died in hepatic coma and found that these patients presented an alteration in glutamate uptake that increased glutamate activity.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Several mechanisms are involved in the uptake of glutamate in astrocytes (<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>). In experimental liver damage, after portocaval anastomosis, a decrease in mRNA and protein expression of the glutamate transporter EAAT-2 has been documented<a class="elsevierStyleCrossRef" href="#bib0080">16</a> and similar results have been obtained after ammonia intoxication. In addition, Suarez et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> reported that portacaval anastomosis in rats decreases the expression of several glutamate transporters (EAAT-1, EAAT-2, EAAT-3 and EAAC-1). Also, Bender and Noren-berg showed that exposure to ammonia of primary cultures of astrocytes, produces a significant decrease in the high affinity uptake of glutamate.<a class="elsevierStyleCrossRef" href="#bib0090">18</a><elsevierMultimedia ident="f0005"></elsevierMultimedia>Chan et al. demonstrated that the high affinity uptake of glutamate and the astrocytic glutamate transporter GLT-I is decreased in brain when concentrations of ammonia are the same as those reported in brain in acute liver failure. Decreased expression of GLT-1 results in increased extracellular brain glutamate concentrations.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>Also, an increase in extracellular glutamate, as that found in patients with acute liver encephalopathy, emphasizes the importance of ammonia and calcium ions, as well as of pH in the release of glutamate.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>An interesting point found by Tofteng et al. is that patients with intracranial hypertension correlate with high levels of extracellular glutamate in brain.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>Using different models of liver injury, glutamate concentration was found increased in brain tissue and cere-brospinal fluid<a class="elsevierStyleCrossRef" href="#bib0110">22</a>,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> in hepatic devascularization<a class="elsevierStyleCrossRef" href="#bib0120">24</a> and in animals exposed to acute hyperammonemia.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>Interestingly, mild hypothermia in rats prevents the initiation of encephalopathy and brain edema, with a decrease in extracellular brain glutamate.<a class="elsevierStyleCrossRef" href="#bib0130">26</a>,<a class="elsevierStyleCrossRef" href="#bib0135">27</a>The NMDA receptorGlutamate has two main types of receptors: ionotropic and metabotropic. There are three key types of ionotropic glutamate receptors: NMDA, AMPA and kainate receptor, being the first one implicated in the control of cerebral processes such as neuronal plasticity, learning and memory.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Metabotropic glutamate receptors are coupled to G proteins and their activation modulates the activity of different enzymes (phospholipase C, adenylate cyclase, etc.) and ion channels through these G proteins, resulting in the modulation of the intracellular levels of second messengers such as diacylglycerol, inositol triphosphates, cAMP, etc. These types of receptors are involved in modulation of motor function, as well.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia can modify the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication leads to an excessive activation of NMDA receptors, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of the signal transduction associated with NMDA receptors.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>Activation of NMDA receptors by glutamate leads to increased intracellular Ca2+ in the post-synaptic neurons. Ca2+ binds to calmodulin and activates different enzymes, including nitric oxide synthetase, leading to improved formation of nitric oxide, which activates soluble guanylate cyclase and increases cGMP. According to Felipo et al., this glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of HE.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> The impairment of this pathway leads to reduced cGMP levels and contributes to impaired cognitive function in hepatic encephalopathy.The mitochondrial dysfunction, as a result of an excitotoxic stress, is produced by the over-activation of the NMDA receptor. Calcium homeostasis, ATP production, and formation and detoxification of reactive oxygen species (ROS) participate in this mechanism.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>The glutamate-glutamine cycleThe glutamate-glutamine cycle (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>) is central to our understanding of brain glutamate metabolism and its relation with the brain alteration of HE syndrome. This cycle is fundamental for the detoxification of ammonia.<elsevierMultimedia ident="f0010"></elsevierMultimedia>The persistence of modified extracellular and intracellular glutamate concentrations also alter the surrounding glial processes, and associated to intrinsic and extrinsic factors may represent the possible first step to apoptosis.It must always be considered that brain damage associated with liver injury can be associated with apoptotic changes where mitochondria fundamentally participate.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Another enzyme involved in glutamate metabolism is glutaminase, an enzyme expressed principally by neurons. Glutamate content in cultured cortical neurons diminishes when exposed to ammonia;<a class="elsevierStyleCrossRef" href="#bib0160">32</a> besides, this toxic inhibits phosphate-activated glutaminase.Ammonia induces depletion of brain glutamate by impairing the malate-aspartate shuttle, which is in charge of the transfer of equivalents between mitochondria and cytosol, ameliorating the reduction of the pyruvate/lactate ratio in cultured astrocytes.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>Morphologically, the blood brain barrier (BBB) is constituted by end feet of astrocytes and endothelial cells with its tight junctions, and apparently is also a target in HE. Glutamate is synthesized in brain from glucose.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> At physiologic plasma concentrations; glutamate flux from plasma into brain is mediated by a high affinity transport system at the BBB. Reverse flux, from brain into plasma, appears to be driven principally by a sodium-dependent active transport system at the capillary abluminal membrane.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> As demonstrated by Scorticati<a class="elsevierStyleCrossRef" href="#bib0180">36</a> and Eizayaga,<a class="elsevierStyleCrossRef" href="#bib0185">37</a> in portal hypertensive rats, BBB increases its permeability. It is thus possible that in this condition glutamate can pass easily from one side to the other of this barrier. Portal hypertension and HE, which are usually present in chronic hepatic disease, allow the easy access of blood vessel contents to neurons and astrocytes.Glutamine and its relation with brain edemaGlutamine, a neutral amino acid, is normally a non-toxic ammonia carrier in the CNS<a class="elsevierStyleCrossRef" href="#bib0190">38</a>,<a class="elsevierStyleCrossRef" href="#bib0195">39</a> and its synthesis represents an astrocyte protection to neurons during increases of blood ammonia concentrations.The osmotic action of glutamine appears to be responsible for cerebral edema and edema-associated disturbances of cerebral blood flow and ionic homeostasis.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>Vasogenic and cytotoxic mechanisms are implicated in the development of cerebral edema. Vasogenic brain edema occurs as a result of the disruption of the BBB, allowing unrestrained access of plasma components and water to the extracellular cerebral compartment. Cytotoxic edema is the consequence of impaired cellular osmoregulation in the brain, resulting in an increase of cellular water.There is a good correlation between the increase in glutamine concentration and brain water content. Therefore, an association between ammonia, glutamate and glutamine increases in brain can produce astrocyte swelling in HE, and consequently brain edema.Astrocytes are the most numerous cell types in the brain and occupy about one-third of the cortical volume. Astrocytes are the cells where glutamine synthesis takes place<a class="elsevierStyleCrossRef" href="#bib0035">7</a> and where water accumulates.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Then, glutamine-induced astrocyte swelling is one of the fundamental steps in the production of cerebral edema in HE. The impaired cerebral microcirculation can be the result of hyperammonemia, and the addition of the osmotic effect of glutamine.<a class="elsevierStyleCrossRef" href="#bib0205">41</a>After ammonia infusion, methionine-sulfoximine (MSO) treatment, an inhibitor of glutamine synthetase activity, reduces swelling in the rat brain, and prevents the increase in intracranial pressure, when fulminant liver failure or portosystemic anastomosis is present.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> According to Hawkins et al. (1993), in portocaval anastomosed rats pretreated with MSO, an increase in tryptophan uptake is induced, suggesting that the uptake of this amino acid is probably produced by an increase in glutamine content in the brain.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> Actually, the association of ammonia and glutamine seems to be necessary to induce brain edema.Interestingly, Warren and Shenker observed that the inhibition of glutamine synthetase decreased the death rate of rats intoxicated with ammonia, ameliorating cerebral edema, astrocyte swelling and seizures,<a class="elsevierStyleCrossRef" href="#bib0220">44</a> thus suggesting that some of its bio-products are harmful to brain metabolism.A good correlation between cerebral glutamine concentration and severity of psychoneurological signs has been found in cirrhotic patients with hyperammonemia;<a class="elsevierStyleCrossRef" href="#bib0225">45</a> besides, glutamine concentration in brain correlates with intracranial pressure measurements.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>According to Albrecht and Norenberg,<a class="elsevierStyleCrossRef" href="#bib0230">46</a> glutamine-mediated ROS production and the mitochondrial permeability transition (MPT) formation are key factors in the production of astrocyte swelling in the presence of ammonia and they proposed the existence of a cascade of events initiated by ROS and MPT.It is interesting that preventing glutamine degradation in brain mitochondria and glutamine uptake can ameliorate brain damage in HE.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>According to Detry et al., it can be hypothesized that brain edema secondary to the osmotic effect of glutamine in astrocytes, and cerebral hyperemia, secondary to vasodilation (cytokines, products of the necrotic liver, glutamine and others) may contribute to intracranial hypertension leading to brain stem herniation and brain death in fulminant hepatic failure.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>Glutamine synthetaseGlutamine synthetase (GS) is a key enzyme in glutamate metabolism (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>), and its decreased activity leads to glutamate increases in the extracellular space. Then, the synthesis of glutamine from glutamate and ammonia in the brain is an important step for detoxification of ammonia in hepatic failure with hyperammonemia.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Glutamine synthesis takes place in astrocytes and maintains glutamate homeostasis in the brain, avoiding an excess of this amino acid, and thus an excitotoxic condition. Glutamine has a short half-life and its activity is regulated and modulated by several mediators and hormones.Nevertheless, as it occurs in severe liver insufficiency, brain astrocytes are injured, morphologically and functionally, and actually GS activity must be involved in this damage.Derouiche and Frotscher have suggested that extracellular glutamate can regulate GS distribution, and that glutamate influences the perisynaptic astrocytic processes with the production of damage in glutamatergic zones.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>A correct functioning of glutamine synthetase in astrocytes leads to a decrease in hyperammonia, and consequently, to a decrease in brain glutamate concentration; in contrast an altered functioning of this pathway allows glutamate to increase.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>Oxidative stress in brainReactive oxygen species have been implicated in the pathophysiology of acute and chronic liver disease.The existence of an oxidative stress (OS) interferes with many nervous cell functions, creating an up-regulation of cytokines and adhesion molecules, and inducing the presence of pro-apoptotic proteins.Murthy et al.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> and Song et al.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> demonstrated the presence of OS in brain tissue in the presence of liver failure. Blanc et al. observed that in liver damage, the activity of glutamate transporters is also impaired.<a class="elsevierStyleCrossRef" href="#bib0265">53</a>Mitochondrial dysfunction and morphological damage is present, and MPT can be formed with the consequent extrusion of its matrix content.<a class="elsevierStyleCrossRef" href="#bib0270">54</a>OS is responsible, then, for the MPT production in mitochondria, and lipid and protein peroxidation in its membranes.According to Tirosh et al.,<a class="elsevierStyleCrossRef" href="#bib0275">55</a> HT4 cells obtained from mouse hippocampal brain region, exposed to glutamate for twelve hours, produce a rapid loss of intracellular reduced glutathione. This is followed by an intracellular accumulation of ROS, increases in intracellular Ca2+, loss of mitochondrial membrane potential and swelling.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>TNF•, ceramide and bile acids enhance ROS production, as well.OS depletes ATP by inhibiting glycogenesis, thus producing an important energy deficiency. The result of the presence of ROS depends on the number of cells involved and the functioning of the anti-stress systems, an adequate glutathione system, a correct antitoxic mechanism, and the activities of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase.OS participates as a critical factor in the mechanism of HE production, especially in hyperammonemic conditions.<a class="elsevierStyleCrossRef" href="#bib0280">56</a>,<a class="elsevierStyleCrossRef" href="#bib0285">57</a>Increased brain production of nitric oxide has been found in rat portocaval anastomosis, which can also participate in the formation of OS.Recently, in a clinical study in which we studied 30 cirrhotic patients, we showed that among those with liver decompensation, OS parameters demonstrated a significant increase, as shown by the presence of the thiobarbituric acid reactive substances, and a decrease in catalase and glutathione peroxidase activity, from the antioxidant enzymes system.<a class="elsevierStyleCrossRef" href="#bib0290">58</a>Apparently, there is no clear evidence for the loss of high-energy phosphates in liver damage, although there are defects in the tricarboxylic acid cycle.<a class="elsevierStyleCrossRef" href="#bib0295">59</a>Manganese accumulation in brain structures has also been implicated in liver failure brain damage.<a class="elsevierStyleCrossRef" href="#bib0300">60</a>,<a class="elsevierStyleCrossRef" href="#bib0305">61</a>ConclusionThe metabolic alterations that appear in HE can be reversible if the brain damage is not extensive and if the time of toxins action is not prolonged.In agreement with Abou-Assi and Vlahcevic, we think that brains of patients with chronic liver disease present impairments in more than a few metabolic pathways, a fact that could explain, in part, the neuropsychiatric signs found in HE.Finally, taking all these experimental and clinical data together, it can be suggested that ammonia is not the only toxic agent that induces HE, but several other substances participate in the development of the encephalopathic syndrome in liver acute and chronic damage, namely the increase in the excitotoxic glutamate levels, the increased concentration of glutamine and the emergence of ROS. It must be recalled that the presence of oxidative stress in brain without adequate defenses aggravates the CNS condition." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1212000" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1128070" "titulo" => "Key words" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Abbreviations" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Introduction" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "The key role of ammonia" ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "Glutamate metabolism alteration" ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Astrocytic glutamate transporters" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "The NMDA receptor" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "The glutamate-glutamine cycle" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Glutamine and its relation with brain edema" ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Glutamine synthetase" ] 11 => array:2 [ "identificador" => "sec0050" "titulo" => "Oxidative stress in brain" ] 12 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusion" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2009-01-27" "fechaAceptado" => "2009-02-22" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Key words" "identificador" => "xpalclavsec1128070" "palabras" => array:7 [ 0 => "Liver" 1 => "brain" 2 => "mitochondria" 3 => "hyperam-monemia" 4 => "glutamine/glutamate cycle" 5 => "excitotoxic neurotransmitter" 6 => "reactive oxygen species" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "This review addresses recent and not so recent works that emphasize on the mechanisms by which liver damage can induce encephalopathy. Hepatic encephalopathy constitutes an intriguing complication in severe liver acute and chronic disease, whose pathophysiology is still not completely understood. In this pathology, alterations in normal brain function are associated with morphological and functional impairments of astrocytes and neurons. A wide spectrum of psychoneurological symptoms has been described and the anatomical substratum is usually associated with brain edema and intracranial hypertension, as well as with changes in the function of brain cells. An increase in blood ammonia, toxic to the brain, depends on the activity of the enzyme glutamine synthetase, the glutamine/glutamate cycle and the brain capacity to eliminate toxic substances. When the concentration of the excitotoxic neurotransmitter glutamate is increased, it acts as a toxic agent, especially when its specific transporters are altered and its uptake is decreased. Glutamine has also been recently considered a toxic substance when its concentration is high, and consequently contributes to brain edema. Finally, the formation of reactive oxygen species, basically produced by mitochondria, influence with their toxic action on membrane lipids, proteins and DNA. In conclusion we suggest that at least these four elements are involved directly in the mechanism of hepatic encephalopathy." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 984 "Ancho" => 1417 "Tamanyo" => 109572 ] ] "descripcion" => array:1 [ "en" => "Glutamate release mechanism in astrocytes. Simplified representation of the six-glutamate release mechanism: aswelling-induced opening of volumeregulated anion channels [VRAC]; bCa2+-dependent exocytosis; creverse operation of excitatory amino acid transporters [EAAT]; d-the cystine-glutamate exchanger; e-connexin hemichannels and f-the P2X7 receptor." ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 864 "Ancho" => 1386 "Tamanyo" => 92939 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of the glutamate-glutamine cycle. According to this formulation, glutamate released upon stimulation from presynaptic terminals into the synaptic cleft can activate glutamate receptors [METAB: metabotropic; NMDA and non-NMDA] on post-synaptic neuron or astrocyte. The uptake of glutamate is mediated by the astrocytic glutamate transporters: EAA1 and EAA2. In astrocytes, glutamate is converted to glutamine via the glutamine synthetase pathway. The glutamine is released back to the neurons, where glutamate is regenerated via phosphate-dependent glutaminase, a mitochondrial enzyme." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:61 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic encephalopathy forward to the past." 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Abraham Lemberg1,

Corresponding author

allef2002@yahoo.com.ar

Address for correspondence:

, Maria Alejandra Fernández1

1 Department of Pathophysiology. School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina

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          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Glutamate release mechanism in astrocytes&#46; Simplified representation of the six-glutamate release mechanism&#58; aswelling-induced opening of volumeregulated anion channels &#91;VRAC&#93;&#59; bCa<span class="elsevierStyleSup">2&#43;</span>-dependent exocytosis&#59; creverse operation of excitatory amino acid transporters &#91;EAAT&#93;&#59; d-the cystine-glutamate exchanger&#59; e-connexin hemichannels and f-the P2X<span class="elsevierStyleInf">7</span> receptor&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Abbreviations</span><p id="p0005" class="elsevierStylePara elsevierViewall">HE&#58; hepatic encephalopathy</p><p id="p0010" class="elsevierStylePara elsevierViewall">CNS&#58; central nervous system</p><p id="p0015" class="elsevierStylePara elsevierViewall">iNOS&#58; inducible nitric oxide synthase</p><p id="p0020" class="elsevierStylePara elsevierViewall">ROS&#58; reactive oxygen species</p><p id="p0025" class="elsevierStylePara elsevierViewall">BBB&#58; blood brain barrier</p><p id="p0030" class="elsevierStylePara elsevierViewall">MSO&#58; methionine-sulfoximine</p><p id="p0035" class="elsevierStylePara elsevierViewall">MPT&#58; mitochondrial permeability transition</p><p id="p0040" class="elsevierStylePara elsevierViewall">GS&#58; glutamine synthetase</p><p id="p0045" class="elsevierStylePara elsevierViewall">OS&#58; oxidative stress</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="p0050" class="elsevierStylePara elsevierViewall">Hepatic encephalopathy &#40;HE&#41; with subclinical and clinical symptoms constitutes a serious complication in the evolution of acute and chronic hepatic failure&#46; The precise pathophysiological mechanism responsible for HE is not completely understood&#44; and sequential events&#44; cascades and pathways must be clarified before a complete answer is obtained&#46;</p><p id="p0055" class="elsevierStylePara elsevierViewall">Alterations in normal brain function following hepatic injury represent a wide spectrum of psychoneurological symptoms that range from somnolence and excitation to confusion and coma&#44; and are usually caused by brain edema&#44; intracranial hypertension and changes in the function and morphology of brain cells&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">In the early years of the twentieth century&#44; the Russian physiologist Ivan Pavlov described the association of the Eck&#8217;s fistula &#40;portacaval anastomosis in dogs&#41; with the presence of ammonia&#44; which shunted into the blood from the intestine&#44;</p><p id="p0065" class="elsevierStylePara elsevierViewall">&#40;Blendis&#44; 2006&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The pathogenic role of portosystemic shunts and elevated blood ammonia concentrations are part of the hepatic encephalopathy syndrome&#46;</p><p id="p0070" class="elsevierStylePara elsevierViewall">Hepatic encephalopathy&#44; as present in fulminant liver failure&#44; appears in acute form&#44; with rapid evolution to coma&#44; seizures&#44; and a high mortality rate&#46; It usually follows cerebral herniation due to intracranial hypertension and hypoxia&#46; A second form of HE presents a slower onset and milder symptoms and can be reversible&#46; A third form of HE presents a chronic evolution with a prolonged persistence of neuropsychiatry symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Another form&#44; a subclinical HE or mild encephalopathy with superficial neuropsychiatric symptoms&#44; which must be recognized to avoid further progression&#44; has also been described&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">Acute and chronic liver failure are associated with many biochemical abnormalities in plasma and brain tissue&#44; which partially explains why the presence of abnormal substances correlate well with the occurrence of memory and behavioral impairments&#44; as observed even with moderate ammonia blood levels in HE&#46;</p><p id="p0080" class="elsevierStylePara elsevierViewall">Among these substances&#44; different concentrations of ammonia&#44; amino acids and neurotransmitters as serotonin&#44; glutamate&#44; glutamine and intermediary metabolites &#40;lactate and pyruvate&#41; can be found&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">In normal subjects&#44; intestinal ammonia&#44; produced from nitrogen products&#44; is taken up by the liver and metabolized to urea&#46; Damaged livers do not accomplish this step adequately&#44; and pathologies as cirrhosis and portal vein thrombosis do not allow splanchnic blood flow to penetrate into the parenchyma&#59; then&#44; portosystemic shunts are created and ammonia and other metabolites are sent to the systemic circulation and finally reach the brain&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">In congenital urea cycle disorders&#44; as seen in children with inborn errors of urea cycle enzymes&#44; blood ammonia levels rise soon after birth&#46;</p><p id="p0095" class="elsevierStylePara elsevierViewall">In the hepatic acinus&#44; urea and glutamine metabolism are heterogeneously distributed&#44; being urea synthesis and the enzyme glutaminase periportally localized and glutamine synthetase perivenously localized&#46; Then&#44; the periportal region has a low affinity but a high capacity for ammonia detoxification&#46; Liver glutamine synthetase acts as a scavenger agent for ammonia&#44; and when liver insuffiency is present&#44; a diminished scavenger capacity takes place&#46;</p><p id="p0100" class="elsevierStylePara elsevierViewall">Brain tissue does not have an effective urea cycle&#44; and then the glutamine synthetase from astrocytes is in charge of ammonia and other toxic substances detoxification&#44; as well&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">The key role of ammonia</span><p id="p0105" class="elsevierStylePara elsevierViewall">Some years ago&#44; we observed that not always blood ammonia levels correlate with the degree of psychoneurological symptoms in liver cirrhosis&#46; As a result of these observations we decided to use the brain isoenzyme of creatinine kinase as an approximate marker of brain impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Our results indicated a good relationship between liver failure and the blood concentration of this isoenzyme&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">Abou-Assi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> reported that&#44; in some cases&#44; there is a lack of correlation between blood ammonia levels and stages of HE&#44; presuming that there are other factors that participate in HE pathophysiology&#46;</p><p id="p0115" class="elsevierStylePara elsevierViewall">Forty per cent of ammonia is generated by the intestine from nitrogenate substances&#44; caused by the action of bacterial urease and amino acid oxidases&#44; and the other 60&#37; is derived from the metabolism of glutamine and the transamination of other amino acids&#46;</p><p id="p0120" class="elsevierStylePara elsevierViewall">Normally&#44; the efficiency by which liver removes intestinal ammonia maintains it at a low blood concentration&#46; Besides&#44; ammonia is generated as a metabolite product in other cells&#44; especially in muscles&#46; It must be recalled that muscles may remove ammonia ions from blood&#44; changing its plasma concentration&#46; The reactions that are catalyzed by the enzyme glutamate dehydrogenase&#44; glutaminase and AMP-deaminase generate important amounts of ammonia&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="p0125" class="elsevierStylePara elsevierViewall">Ammonia either enters the brain by diffusion from the blood or cerebrospinal fluid or is formed <span class="elsevierStyleItalic">in situ</span> from the metabolism of endogenous nitrogen-containing substances&#46; Its excess is toxic to the central nervous system &#40;CNS&#41;&#46; As the brain does not produce urea from ammonia&#44; its removal relies almost exclusively on glutamine synthetase&#44; basically localized in astrocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0130" class="elsevierStylePara elsevierViewall">It has been demonstrated in several studies that ammonia ions participate actively in neuron-astrocyte metabolic interaction&#44; specifically in the functioning of the glutamate&#47;glutamine cycle&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="p0135" class="elsevierStylePara elsevierViewall">The morphopathological findings in HE and other hyperammonemic conditions are localized in astrocytes rather than in neurons&#46; The Alzheimer type II astrocyte change is the distinctive morphological alteration in brain of cirrhotic astrocytes&#44; hyperammonemic congenical pathologies and urea cycle disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="p0140" class="elsevierStylePara elsevierViewall">The experimental findings by Cummins et al&#46; are&#44; to a certain extent&#44; similar to our results obtained with our model of encephalopathy and prehepatic portal hypertension&#44; with low ammonia concentration and brain damage&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0145" class="elsevierStylePara elsevierViewall">Ammonia toxic effects act inhibiting the tricarboxylic acid cycle enzymes&#44; &#8226;-ketoglutarate dehydrogenase &#40;<span class="elsevierStyleItalic">in vitro</span>&#41;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and stimulate phospho-fructokinase and other glycolytic enzymes in brain tissue&#46;</p><p id="p0150" class="elsevierStylePara elsevierViewall">Ammonia inhibits excitatory post-synaptic potentials&#44; thereby&#44; producing a general depression of the CNS function&#59; and high levels produce brain energy failure due to its inhibitory action on key tricarboxylic acid cycle enzymes&#46;</p><p id="p0155" class="elsevierStylePara elsevierViewall">The metabolism of ammonia to glutamine appears to be necessary&#44; and is followed by an osmotic disturbance in the brain&#44; mitochondrial dysfunction with oxidative stress&#44; and alterations in brain glucose metabolism&#46; Cerebral blood flow is also altered and strongly influences the development of brain edema and intracranial hypertension&#46; Added factors&#44; such as systemic inflammation&#44; alterations in the brain extracellular concentration of amino acids and neurotransmitters&#44; may contribute to the cerebral alterations in acute liver failure&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0160" class="elsevierStylePara elsevierViewall">Elevated brain ammonia level is an important etiologic factor in astrocyte swelling and brain edema&#44; the main neuropathological findings in the acute form of hepatic encephalopathy&#46; One factor known to be activated by oxidative&#47;nitrosative stress and mitogen-activated protein kinases &#40;both considered important elements in astrocyte swelling&#41; is nuclear factor kappaB a transcription factor that activates the inducible nitric oxide synthase &#40;iNOS&#41; and other genes&#46; Nitric oxide&#44; the product of iNOS&#44; is known to cause astrocyte swelling&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="p0165" class="elsevierStylePara elsevierViewall">G&#246;rg et al&#46; identified the cerebral RNA oxidation as a not yet recognized consequence of acute ammonia intoxication&#46; RNA oxidation may affect gene expression and local protein synthesis&#44; and may thereby provide another link between reactive oxygen species&#47;reactive nitrogen oxide species production&#44; and ammonia toxicity&#46; Also&#44; oxidized RNA species may participate in post-synaptic protein synthesis&#44; which is normally a biochemical substrate for learning and memory consolidation&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="p0170" class="elsevierStylePara elsevierViewall">Bai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> have proposed that ammonia induces the mitochondrial permeability transition in cultured astrocytes&#44; which may be a factor in the mitochondrial dysfunction associated with HE and other hyperammonemic states &#40;see below&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Glutamate metabolism alteration</span><p id="p0175" class="elsevierStylePara elsevierViewall">Glutamate is the main excitatory neurotransmitter in the mammalian CNS&#46; Glutamate modulates several brain processes&#44; including the encoding of information&#44; the formation and retrieval of memories&#44; spatial recognition and the maintenance of consciousness&#46;</p><p id="p0180" class="elsevierStylePara elsevierViewall">Glutamatergic neurotransmission involves several steps&#44; beginning with the release of glutamate from the pre-synaptic neuron&#59; its presence in the extracellular space activates glutamate receptors present in the synaptic membranes&#44; leading to activation of signal transduction pathways related to these receptors&#46; Glutamate is removed from the synaptic cleft by specific glutamate transporters located mainly in astrocytes&#44; avoiding overstimulation of glutamate receptors&#46; The alterations in any of these steps may result in impairment of glutamatergic neurotransmission&#44; leading to neurological alterations&#44; especially those seen in neurodegenerative disease&#46; In addition&#44; the increased excitotoxicity of glutamate produces brain damage&#44; as it also occurs in brain ischemia&#44; anoxia and trauma&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Astrocytic glutamate transporters</span><p id="p0185" class="elsevierStylePara elsevierViewall">There is increasing evidence implying that HE in acute liver failure is the result of altered glutamatergic function&#46; Brain glutamate metabolism constitutes its synthesis&#44; uptake and release&#44; and depends on the last two steps on the normal transporter function&#59; then again&#44; toxic substances and abnormal detoxification mechanisms are responsible for HE syndrome&#46;</p><p id="p0190" class="elsevierStylePara elsevierViewall">Schmidt et al&#46; studied hippocampal slices exposed to serum and cerebrospinal fluid obtained from patients with chronic liver disease who had died in hepatic coma and found that these patients presented an alteration in glutamate uptake that increased glutamate activity&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="p0195" class="elsevierStylePara elsevierViewall">Several mechanisms are involved in the uptake of glutamate in astrocytes &#40;<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>&#41;&#46; In experimental liver damage&#44; after portocaval anastomosis&#44; a decrease in mRNA and protein expression of the glutamate transporter EAAT-2 has been documented<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and similar results have been obtained after ammonia intoxication&#46; In addition&#44; Suarez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> reported that portacaval anastomosis in rats decreases the expression of several glutamate transporters &#40;EAAT-1&#44; EAAT-2&#44; EAAT-3 and EAAC-1&#41;&#46; Also&#44; Bender and Noren-berg showed that exposure to ammonia of primary cultures of astrocytes&#44; produces a significant decrease in the high affinity uptake of glutamate&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0200" class="elsevierStylePara elsevierViewall">Chan et al&#46; demonstrated that the high affinity uptake of glutamate and the astrocytic glutamate transporter GLT-I is decreased in brain when concentrations of ammonia are the same as those reported in brain in acute liver failure&#46; Decreased expression of GLT-1 results in increased extracellular brain glutamate concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="p0205" class="elsevierStylePara elsevierViewall">Also&#44; an increase in extracellular glutamate&#44; as that found in patients with acute liver encephalopathy&#44; emphasizes the importance of ammonia and calcium ions&#44; as well as of pH in the release of glutamate&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0210" class="elsevierStylePara elsevierViewall">An interesting point found by Tofteng et al&#46; is that patients with intracranial hypertension correlate with high levels of extracellular glutamate in brain&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="p0215" class="elsevierStylePara elsevierViewall">Using different models of liver injury&#44; glutamate concentration was found increased in brain tissue and cere-brospinal fluid<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> in hepatic devascularization<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and in animals exposed to acute hyperammonemia&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="p0220" class="elsevierStylePara elsevierViewall">Interestingly&#44; mild hypothermia in rats prevents the initiation of encephalopathy and brain edema&#44; with a decrease in extracellular brain glutamate&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The NMDA receptor</span><p id="p0225" class="elsevierStylePara elsevierViewall">Glutamate has two main types of receptors&#58; ionotropic and metabotropic&#46; There are three key types of ionotropic glutamate receptors&#58; NMDA&#44; AMPA and kainate receptor&#44; being the first one implicated in the control of cerebral processes such as neuronal plasticity&#44; learning and memory&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Metabotropic glutamate receptors are coupled to G proteins and their activation modulates the activity of different enzymes &#40;phospholipase C&#44; adenylate cyclase&#44; etc&#46;&#41; and ion channels through these G proteins&#44; resulting in the modulation of the intracellular levels of second messengers such as diacylglycerol&#44; inositol triphosphates&#44; cAMP&#44; etc&#46; These types of receptors are involved in modulation of motor function&#44; as well&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="p0230" class="elsevierStylePara elsevierViewall">Excessive activation of NMDA receptors leads to neuronal degeneration and death&#46; Hyperammonemia can modify the function of NMDA receptors and of some associated signal transduction pathways&#46; The alterations are different in acute and chronic hyperammonemia and liver failure&#46; Acute intoxication leads to an excessive activation of NMDA receptors&#44; which is responsible for ammonia-induced death&#46; In contrast&#44; chronic hyperammonemia induces adaptive responses resulting in impairment of the signal transduction associated with NMDA receptors&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="p0235" class="elsevierStylePara elsevierViewall">Activation of NMDA receptors by glutamate leads to increased intracellular Ca2&#43; in the post-synaptic neurons&#46; Ca2&#43; binds to calmodulin and activates different enzymes&#44; including nitric oxide synthetase&#44; leading to improved formation of nitric oxide&#44; which activates soluble guanylate cyclase and increases cGMP&#46; According to Felipo et al&#46;&#44; this glutamate-nitric oxide-cGMP pathway is impaired in brain <span class="elsevierStyleItalic">in vivo</span> in animal models of HE&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The impairment of this pathway leads to reduced cGMP levels and contributes to impaired cognitive function in hepatic encephalopathy&#46;</p><p id="p0240" class="elsevierStylePara elsevierViewall">The mitochondrial dysfunction&#44; as a result of an excitotoxic stress&#44; is produced by the over-activation of the NMDA receptor&#46; Calcium homeostasis&#44; ATP production&#44; and formation and detoxification of reactive oxygen species &#40;ROS&#41; participate in this mechanism&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">The glutamate-glutamine cycle</span><p id="p0245" class="elsevierStylePara elsevierViewall">The glutamate-glutamine cycle &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>&#41; is central to our understanding of brain glutamate metabolism and its relation with the brain alteration of HE syndrome&#46; This cycle is fundamental for the detoxification of ammonia&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0250" class="elsevierStylePara elsevierViewall">The persistence of modified extracellular and intracellular glutamate concentrations also alter the surrounding glial processes&#44; and associated to intrinsic and extrinsic factors may represent the possible first step to apoptosis&#46;</p><p id="p0255" class="elsevierStylePara elsevierViewall">It must always be considered that brain damage associated with liver injury can be associated with apoptotic changes where mitochondria fundamentally participate&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="p0260" class="elsevierStylePara elsevierViewall">Another enzyme involved in glutamate metabolism is glutaminase&#44; an enzyme expressed principally by neurons&#46; Glutamate content in cultured cortical neurons diminishes when exposed to ammonia&#59;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> besides&#44; this toxic inhibits phosphate-activated glutaminase&#46;</p><p id="p0265" class="elsevierStylePara elsevierViewall">Ammonia induces depletion of brain glutamate by impairing the malate-aspartate shuttle&#44; which is in charge of the transfer of equivalents between mitochondria and cytosol&#44; ameliorating the reduction of the pyruvate&#47;lactate ratio in cultured astrocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="p0270" class="elsevierStylePara elsevierViewall">Morphologically&#44; the blood brain barrier &#40;BBB&#41; is constituted by end feet of astrocytes and endothelial cells with its tight junctions&#44; and apparently is also a target in HE&#46; Glutamate is synthesized in brain from glucose&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> At physiologic plasma concentrations&#59; glutamate flux from plasma into brain is mediated by a high affinity transport system at the BBB&#46; Reverse flux&#44; from brain into plasma&#44; appears to be driven principally by a sodium-dependent active transport system at the capillary abluminal membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> As demonstrated by Scorticati<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> and Eizayaga&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> in portal hypertensive rats&#44; BBB increases its permeability&#46; It is thus possible that in this condition glutamate can pass easily from one side to the other of this barrier&#46; Portal hypertension and HE&#44; which are usually present in chronic hepatic disease&#44; allow the easy access of blood vessel contents to neurons and astrocytes&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Glutamine and its relation with brain edema</span><p id="p0275" class="elsevierStylePara elsevierViewall">Glutamine&#44; a neutral amino acid&#44; is normally a non-toxic ammonia carrier in the CNS<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> and its synthesis represents an astrocyte protection to neurons during increases of blood ammonia concentrations&#46;</p><p id="p0280" class="elsevierStylePara elsevierViewall">The osmotic action of glutamine appears to be responsible for cerebral edema and edema-associated disturbances of cerebral blood flow and ionic homeostasis&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="p0285" class="elsevierStylePara elsevierViewall">Vasogenic and cytotoxic mechanisms are implicated in the development of cerebral edema&#46; Vasogenic brain edema occurs as a result of the disruption of the BBB&#44; allowing unrestrained access of plasma components and water to the extracellular cerebral compartment&#46; Cytotoxic edema is the consequence of impaired cellular osmoregulation in the brain&#44; resulting in an increase of cellular water&#46;</p><p id="p0290" class="elsevierStylePara elsevierViewall">There is a good correlation between the increase in glutamine concentration and brain water content&#46; Therefore&#44; an association between ammonia&#44; glutamate and glutamine increases in brain can produce astrocyte swelling in HE&#44; and consequently brain edema&#46;</p><p id="p0295" class="elsevierStylePara elsevierViewall">Astrocytes are the most numerous cell types in the brain and occupy about one-third of the cortical volume&#46; Astrocytes are the cells where glutamine synthesis takes place<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and where water accumulates&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Then&#44; glutamine-induced astrocyte swelling is one of the fundamental steps in the production of cerebral edema in HE&#46; The impaired cerebral microcirculation can be the result of hyperammonemia&#44; and the addition of the osmotic effect of glutamine&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="p0300" class="elsevierStylePara elsevierViewall">After ammonia infusion&#44; methionine-sulfoximine &#40;MSO&#41; treatment&#44; an inhibitor of glutamine synthetase activity&#44; reduces swelling in the rat brain&#44; and prevents the increase in intracranial pressure&#44; when fulminant liver failure or portosystemic anastomosis is present&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> According to Hawkins et al&#46; &#40;1993&#41;&#44; in portocaval anastomosed rats pretreated with MSO&#44; an increase in tryptophan uptake is induced&#44; suggesting that the uptake of this amino acid is probably produced by an increase in glutamine content in the brain&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Actually&#44; the association of ammonia and glutamine seems to be necessary to induce brain edema&#46;</p><p id="p0305" class="elsevierStylePara elsevierViewall">Interestingly&#44; Warren and Shenker observed that the inhibition of glutamine synthetase decreased the death rate of rats intoxicated with ammonia&#44; ameliorating cerebral edema&#44; astrocyte swelling and seizures&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> thus suggesting that some of its bio-products are harmful to brain metabolism&#46;</p><p id="p0310" class="elsevierStylePara elsevierViewall">A good correlation between cerebral glutamine concentration and severity of psychoneurological signs has been found in cirrhotic patients with hyperammonemia&#59;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> besides&#44; glutamine concentration in brain correlates with intracranial pressure measurements&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="p0315" class="elsevierStylePara elsevierViewall">According to Albrecht and Norenberg&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> glutamine-mediated ROS production and the mitochondrial permeability transition &#40;MPT&#41; formation are key factors in the production of astrocyte swelling in the presence of ammonia and they proposed the existence of a cascade of events initiated by ROS and MPT&#46;</p><p id="p0320" class="elsevierStylePara elsevierViewall">It is interesting that preventing glutamine degradation in brain mitochondria and glutamine uptake can ameliorate brain damage in HE&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="p0325" class="elsevierStylePara elsevierViewall">According to Detry et al&#46;&#44; it can be hypothesized that brain edema secondary to the osmotic effect of glutamine in astrocytes&#44; and cerebral hyperemia&#44; secondary to vasodilation &#40;cytokines&#44; products of the necrotic liver&#44; glutamine and others&#41; may contribute to intracranial hypertension leading to brain stem herniation and brain death in fulminant hepatic failure&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Glutamine synthetase</span><p id="p0330" class="elsevierStylePara elsevierViewall">Glutamine synthetase &#40;GS&#41; is a key enzyme in glutamate metabolism &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>&#41;&#44; and its decreased activity leads to glutamate increases in the extracellular space&#46; Then&#44; the synthesis of glutamine from glutamate and ammonia in the brain is an important step for detoxification of ammonia in hepatic failure with hyperammonemia&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="p0335" class="elsevierStylePara elsevierViewall">Glutamine synthesis takes place in astrocytes and maintains glutamate homeostasis in the brain&#44; avoiding an excess of this amino acid&#44; and thus an excitotoxic condition&#46; Glutamine has a short half-life and its activity is regulated and modulated by several mediators and hormones&#46;</p><p id="p0340" class="elsevierStylePara elsevierViewall">Nevertheless&#44; as it occurs in severe liver insufficiency&#44; brain astrocytes are injured&#44; morphologically and functionally&#44; and actually GS activity must be involved in this damage&#46;</p><p id="p0345" class="elsevierStylePara elsevierViewall">Derouiche and Frotscher have suggested that extracellular glutamate can regulate GS distribution&#44; and that glutamate influences the perisynaptic astrocytic processes with the production of damage in glutamatergic zones&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="p0350" class="elsevierStylePara elsevierViewall">A correct functioning of glutamine synthetase in astrocytes leads to a decrease in hyperammonia&#44; and consequently&#44; to a decrease in brain glutamate concentration&#59; in contrast an altered functioning of this pathway allows glutamate to increase&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Oxidative stress in brain</span><p id="p0355" class="elsevierStylePara elsevierViewall">Reactive oxygen species have been implicated in the pathophysiology of acute and chronic liver disease&#46;</p><p id="p0360" class="elsevierStylePara elsevierViewall">The existence of an oxidative stress &#40;OS&#41; interferes with many nervous cell functions&#44; creating an up-regulation of cytokines and adhesion molecules&#44; and inducing the presence of pro-apoptotic proteins&#46;</p><p id="p0365" class="elsevierStylePara elsevierViewall">Murthy et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> and Song et al&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> demonstrated the presence of OS in brain tissue in the presence of liver failure&#46; Blanc et al&#46; observed that in liver damage&#44; the activity of glutamate transporters is also impaired&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p><p id="p0370" class="elsevierStylePara elsevierViewall">Mitochondrial dysfunction and morphological damage is present&#44; and MPT can be formed with the consequent extrusion of its matrix content&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p><p id="p0375" class="elsevierStylePara elsevierViewall">OS is responsible&#44; then&#44; for the MPT production in mitochondria&#44; and lipid and protein peroxidation in its membranes&#46;</p><p id="p0380" class="elsevierStylePara elsevierViewall">According to Tirosh et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> HT4 cells obtained from mouse hippocampal brain region&#44; exposed to glutamate for twelve hours&#44; produce a rapid loss of intracellular reduced glutathione&#46; This is followed by an intracellular accumulation of ROS&#44; increases in intracellular Ca<span class="elsevierStyleSup">2&#43;</span>&#44; loss of mitochondrial membrane potential and swelling&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="p0385" class="elsevierStylePara elsevierViewall">TNF&#8226;&#44; ceramide and bile acids enhance ROS production&#44; as well&#46;</p><p id="p0390" class="elsevierStylePara elsevierViewall">OS depletes ATP by inhibiting glycogenesis&#44; thus producing an important energy deficiency&#46; The result of the presence of ROS depends on the number of cells involved and the functioning of the anti-stress systems&#44; an adequate glutathione system&#44; a correct antitoxic mechanism&#44; and the activities of antioxidant enzymes such as catalase&#44; superoxide dismutase and glutathione peroxidase&#46;</p><p id="p0395" class="elsevierStylePara elsevierViewall">OS participates as a critical factor in the mechanism of HE production&#44; especially in hyperammonemic conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p><p id="p0400" class="elsevierStylePara elsevierViewall">Increased brain production of nitric oxide has been found in rat portocaval anastomosis&#44; which can also participate in the formation of OS&#46;</p><p id="p0405" class="elsevierStylePara elsevierViewall">Recently&#44; in a clinical study in which we studied 30 cirrhotic patients&#44; we showed that among those with liver decompensation&#44; OS parameters demonstrated a significant increase&#44; as shown by the presence of the thiobarbituric acid reactive substances&#44; and a decrease in catalase and glutathione peroxidase activity&#44; from the antioxidant enzymes system&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p><p id="p0410" class="elsevierStylePara elsevierViewall">Apparently&#44; there is no clear evidence for the loss of high-energy phosphates in liver damage&#44; although there are defects in the tricarboxylic acid cycle&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p><p id="p0415" class="elsevierStylePara elsevierViewall">Manganese accumulation in brain structures has also been implicated in liver failure brain damage&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusion</span><p id="p0420" class="elsevierStylePara elsevierViewall">The metabolic alterations that appear in HE can be reversible if the brain damage is not extensive and if the time of toxins action is not prolonged&#46;</p><p id="p0425" class="elsevierStylePara elsevierViewall">In agreement with Abou-Assi and Vlahcevic&#44; we think that brains of patients with chronic liver disease present impairments in more than a few metabolic pathways&#44; a fact that could explain&#44; in part&#44; the neuropsychiatric signs found in HE&#46;</p><p id="p0430" class="elsevierStylePara elsevierViewall">Finally&#44; taking all these experimental and clinical data together&#44; it can be suggested that ammonia is not the only toxic agent that induces HE&#44; but several other substances participate in the development of the encephalopathic syndrome in liver acute and chronic damage&#44; namely the increase in the excitotoxic glutamate levels&#44; the increased concentration of glutamine and the emergence of ROS&#46; It must be recalled that the presence of oxidative stress in brain without adequate defenses aggravates the CNS condition&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "titulo" => "Abstract"
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              "identificador" => "abs0005"
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          "titulo" => "Key words"
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          "titulo" => "Abbreviations"
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        3 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Introduction"
        ]
        4 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "The key role of ammonia"
        ]
        5 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Glutamate metabolism alteration"
        ]
        6 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Astrocytic glutamate transporters"
        ]
        7 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "The NMDA receptor"
        ]
        8 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "The glutamate-glutamine cycle"
        ]
        9 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Glutamine and its relation with brain edema"
        ]
        10 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Glutamine synthetase"
        ]
        11 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Oxidative stress in brain"
        ]
        12 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conclusion"
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        13 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2009-01-27"
    "fechaAceptado" => "2009-02-22"
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          "clase" => "keyword"
          "titulo" => "Key words"
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          "palabras" => array:7 [
            0 => "Liver"
            1 => "brain"
            2 => "mitochondria"
            3 => "hyperam-monemia"
            4 => "glutamine&#47;glutamate cycle"
            5 => "excitotoxic neurotransmitter"
            6 => "reactive oxygen species"
          ]
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      ]
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    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0005" class="elsevierStyleSection elsevierViewall"><p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">This review addresses recent and not so recent works that emphasize on the mechanisms by which liver damage can induce encephalopathy&#46; Hepatic encephalopathy constitutes an intriguing complication in severe liver acute and chronic disease&#44; whose pathophysiology is still not completely understood&#46; In this pathology&#44; alterations in normal brain function are associated with morphological and functional impairments of astrocytes and neurons&#46; A wide spectrum of psychoneurological symptoms has been described and the anatomical substratum is usually associated with brain edema and intracranial hypertension&#44; as well as with changes in the function of brain cells&#46; An increase in blood ammonia&#44; toxic to the brain&#44; depends on the activity of the enzyme glutamine synthetase&#44; the glutamine&#47;glutamate cycle and the brain capacity to eliminate toxic substances&#46; When the concentration of the excitotoxic neurotransmitter glutamate is increased&#44; it acts as a toxic agent&#44; especially when its specific transporters are altered and its uptake is decreased&#46; Glutamine has also been recently considered a toxic substance when its concentration is high&#44; and consequently contributes to brain edema&#46; Finally&#44; the formation of reactive oxygen species&#44; basically produced by mitochondria&#44; influence with their toxic action on membrane lipids&#44; proteins and DNA&#46; In conclusion we suggest that at least these four elements are involved directly in the mechanism of hepatic encephalopathy&#46;</p></span>"
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        "etiqueta" => "<span class="elsevierStyleBold">Figure 1</span>"
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          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Glutamate release mechanism in astrocytes&#46; Simplified representation of the six-glutamate release mechanism&#58; aswelling-induced opening of volumeregulated anion channels &#91;VRAC&#93;&#59; bCa<span class="elsevierStyleSup">2&#43;</span>-dependent exocytosis&#59; creverse operation of excitatory amino acid transporters &#91;EAAT&#93;&#59; d-the cystine-glutamate exchanger&#59; e-connexin hemichannels and f-the P2X<span class="elsevierStyleInf">7</span> receptor&#46;</p>"
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          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the glutamate-glutamine cycle&#46; According to this formulation&#44; glutamate released upon stimulation from presynaptic terminals into the synaptic cleft can activate glutamate receptors &#91;METAB&#58; metabotropic&#59; NMDA and non-NMDA&#93; on post-synaptic neuron or astrocyte&#46; The uptake of glutamate is mediated by the astrocytic glutamate transporters&#58; EAA1 and EAA2&#46; In astrocytes&#44; glutamate is converted to glutamine via the glutamine synthetase pathway&#46; The glutamine is released back to the neurons&#44; where glutamate is regenerated via phosphate-dependent glutaminase&#44; a mitochondrial enzyme&#46;</p>"
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/S1665-2681(19)31785-5

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Year/Month	Html	Pdf	Total

2024 October	54	15	69
2024 September	87	23	110
2024 August	77	28	105
2024 July	130	22	152
2024 June	135	22	157
2024 May	174	12	186
2024 April	142	13	155
2024 March	159	18	177
2024 February	119	30	149
2024 January	91	16	107
2023 December	82	14	96
2023 November	111	18	129
2023 October	119	19	138
2023 September	64	2	66
2023 August	57	7	64
2023 July	56	9	65
2023 June	51	2	53
2023 May	99	3	102
2023 April	73	10	83
2023 March	70	2	72
2023 February	55	5	60
2023 January	39	12	51
2022 December	40	2	42
2022 November	37	10	47
2022 October	56	10	66
2022 September	40	8	48
2022 August	65	8	73
2022 July	47	12	59
2022 June	39	12	51
2022 May	54	18	72
2022 April	43	8	51
2022 March	68	11	79
2022 February	55	5	60
2022 January	89	5	94
2021 December	52	14	66
2021 November	40	9	49
2021 October	33	11	44
2021 September	46	11	57
2021 August	31	8	39
2021 July	12	7	19
2021 June	17	9	26
2021 May	32	5	37
2021 April	89	17	106
2021 March	48	5	53
2021 February	37	7	44
2021 January	35	20	55
2020 December	40	8	48
2020 November	39	7	46
2020 October	21	8	29
2020 September	28	5	33
2020 August	26	8	34
2020 July	21	2	23
2020 June	11	2	13
2020 May	26	8	34
2020 April	16	0	16
2020 March	10	5	15
2020 February	5	1	6
2020 January	7	3	10
2019 December	3	5	8
2019 November	5	1	6
2019 October	1	1	2
2019 September	1	4	5
2019 August	2	2	4
2019 July	2	11	13

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