Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure

Thumburu, Kiran K.; Dhiman, Radha K.; Vasishta, Rakesh Kumar; Chakraborti, Anuradha; Butterworth, Roger F.; Beauchesne, Élizabeth; Desjardins, Paul; Goyal, Sandeep; Sharma, Navneet; Duseja, Ajay; Chawla, Yogesh

doi:10.1111/jnc.12511

Cited by 33 publications

(32 citation statements)

References 53 publications

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“…Loss of EAAT-2 gene and protein expression was recently reported in autopsied brain tissue from patients with ALF resulting primarily from viral hepatitis. 3 Expression of a second glutamate transporter EAAT-1 was unchanged in this material.…”

Section: Astrocytesmentioning

confidence: 81%

“…27,28 Loss of GFAP expression was recently described in autopsied brain tissue samples from patients who died as a result primarily of brain herniation due to ALF. 3 The astrocyte membrane is home to a range of high affinity amino acid transporters that include transporters for glutamate (EAAT-2), glycine (GLYT-1) and glutamine (SNAT-3 and SNAT-5) Expression of genes coding for many of these proteins has been shown to be downregulated in brain extracts from animals with ALF due to ischemic liver failure. EAAT-2 is a cloned and well characterized high affinity transporter for glutamate that is located on the astrocyte membrane primarily in forebrain of mammals.…”

Section: Astrocytesmentioning

confidence: 99%

“…Studies in experimental animals with ALF due to toxic liver injury show a similar pattern of changes as well as alterations in expression of genes coding for key astrocytic proteins. 3 Although gross alterations of the blood-brain barrier (BBB) are not generally a feature of ALF, alterations of cerebrovascular endothelial cell function have occasionally been described. 2,4 On the other hand, material from ALF animals in which edema and encephalopathy were precipitated by infection manifest clear alterations of both BBB function and of expression of BBB tight junction proteins.…”

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confidence: 99%

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Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Butterworth

2015

Journal of Clinical and Experimental Hepatology

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117

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Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepatoprotective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited. ( J CLIN EXP HEPATOL 2015;5:S96-S103) A cute liver failure (ALF), also referred to as fulminant hepatic failure, invariably leads to central nervous system dysfunction that may include encephalopathy, seizures and brain edema, a major cause of intracranial hypertension and brain herniation, a leading cause of mortality in ALF. An increase in cerebral blood flow frequently accompanies the onset of brain edema. 1Neuropathological assessments of the brain in both human and experimental ALF reveals significant changes to neuroglia in general and to astrocytes and microglia, in particular. Astrocytes in brain sections from patients who died in ALF are swollen 2 as are their mitochondria (Figure 1). Based upon these observations, it is generally assumed that the brain edema that accompanies ALF is primarily, if not exclusively, cytotoxic in nature. Studies in experimental animals with ALF due to toxic liver injury show a similar pattern of changes as well as alterations in expression of genes coding for key astrocytic proteins. 3Although gross alterations of the blood-brain barrier (BBB) are not generally a feature of ALF, alterations of cerebrovascular endothelial cell function have occasionally been described. 2,4 On the other hand, material from ALF animals in which edema and encephalopathy were precipitated by infection manifest clear alterations of both BBB function and of expression of BBB tight junction proteins.5 These latter findings suggest that, in ALF accompanied by significant infection/inflammation, brain edema may comprise both cytotoxic and vasogenic components. BRAIN METABOLISM IN ACUTE LIVER FAILUREALF leads to severe compromise of cerebral metabolism and includes increases of cerebral blood flow, decrea...

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Section: Astrocytesmentioning

confidence: 81%

Section: Astrocytesmentioning

confidence: 99%

mentioning

confidence: 99%

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Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Butterworth

2015

Journal of Clinical and Experimental Hepatology

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117

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“…Number of experimental studies, as well as the study of the autopsy material of patients with ALF demonstrated violation of the expression of several key astrocytic proteins: Aqp-4, GFAP (glial fibrillar acidic protein) [47], glutamine transporter SNAT5, glutamate transporters (GLT-1 (SLC1A2 -solute carrier family 1 member 2; EAAT2 -excitatory amino acid transporter-2)), glycine transporters (GLYT-1), glucose transporters (GLUT-1), peripheral type benzodiazepine receptors [48]. Thus, K. K. Thumburu et al in the study of the cerebral cortex of 8 patients died in ALF showed an increase in the level of Aqp-4 mRNA and Aqp-4 IHC expression in the region of astrocyte microvascular perivascular end-feet, as well as marked decrease in mRNA level and intermediate filament protein GFAP expression on the background of the brain tissue cytotoxic edema pattern.…”

Section: Introductionmentioning

confidence: 99%

Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

Shulyatnikova

Shavrin

2017

Patologìâ

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Background. The problem of acute and chronic forms of hepatic encephalopathy (HE) is not clearly identified among modern problems of hepatology and neuroscience in Ukraine. Despite the significant contribution to the development of lethal complications in patients with liver pathology and long history of the study of this issue, there is still no unified opinion on the links of HE pathogenesis.The aim of this review is to conduct a comprehensive analysis of current data on the spreading and mechanisms of development of HE.HE is a complex of potentially reversible neurocognitive disorders in patients with chronic or acute hepatic failure (ALF). HE is more often a complication of liver cirrhosis and is the second most frequent cause of hospitalization of such patients after ascites. When decompensating liver failure in acute or chronic hepatic pathology in patients severe forms of HE develop, accompanied by a progressive increase in intracranial pressure and the development of coma, which often ends lethal due to poor corrigibility of intracranial hypertension while maintaining hepatogenic neurointoxication. HE is considered as the end result of the accumulation of a number of neurotoxic substances in the brain, among which are ammonia, mercaptans, short chain fatty acids, false neurotransmitters, gamma-aminobutyric acid, manganese. The most popular among the reasons for the development of HE is the neurotoxic theory of ammonia. Ammonia is subjected to detoxification in the liver, turning into urea, a smaller fraction with the participation of glutamine synthetase is used in the synthesis of glutamine in muscles, liver and astrocytes of brain. In case of hepatic dysfunction and/or portosystemic shunting, the concentration of ammonia in blood increases up to 10 times and the main load for its detoxification is shifted to myocytes and astroglia. In ALF glutamine overload of astrocytes occurs with a change in intracellular osmolarity and subsequent edema of astroglia, which is accompanied by the development of cytotoxic edema of the brain. In this case, in astrocytes damaging of mitochondrial respiratory chain occurs and mitochondrial insufficiency develops, as well as processes of nitrosative-oxidative stress and oxidation of astrocytic and neuronal RNA, disruption of gene expression, synthesis of neuro-and gliotransmitters and synaptic plasticity. The increased influx of aromatic amino acids into brain leads to the synthesis of false neurotransmitters, which worsens serotoninergic, GABA-ergic, dopaminergic and glutamatergic neurotransmission. Damage to the components of the blood-brain barrier leads to aggravation of the water imbalance, penetration of hematogenous cytokines, endotoxins and other products of systemic inflammatory reaction into the cerebral parenchyma and development of neuroinflammation, which makes an important contribution to the further progression of cerebral edema.Conclusions: despite a comprehensive study of the problem, many open questions remain in the pathogenesis of HE. Special attention ...

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“…HE is potentially reversible and emerges as the major complication of acute or chronic liver failure (ALF, CLF)[2]. RF Butterworth in his recent review[3] stressed that brain edema that accompanies ALF is the primarily cytotoxic phenomena, and moreover, this correlates with alterations in expression of genes coding for key astrocytic proteins[4]. …”

Section: Introductionmentioning

confidence: 99%

Hepatic encephalopathy: Ever closer to its big bang

Souto¹,

Marcotegui²,

Orbea³

et al. 2016

WJG

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Hepatic encephalopathy (HE) is a neuropsychiatric disorder that commonly complicates the course of patients with liver disease. Despite the fact that the syndrome was probably first recognized hundreds of years ago, the exact pathogenesis still remains unclear. Minimal hepatic encephalopathy (MHE) is the earliest form of HE and is estimated to affect more that 75% of patients with liver cirrhosis. It is characterized by cognitive impairment predominantly attention, reactiveness and integrative function with very subtle clinical manifestations. The development of MHE is associated with worsen in driving skills, daily activities and the increase of overall mortality. Skeletal muscle has the ability to shift from ammonia producer to ammonia detoxifying organ. Due to its large size, becomes the main ammonia detoxifying organ in case of chronic liver failure and muscular glutamine-synthase becomes important due to the failing liver and brain metabolic activity. Gut is the major glutamine consumer and ammonia producer organ in the body. Hepatocellular dysfunction due to liver disease, results in an impaired clearance of ammonium and in its inter-organ trafficking. Intestinal bacteria, can also represent an extra source of ammonia production and in cirrhosis, small intestinal bacterial overgrowth and symbiosis can be observed. In the study of HE, to get close to MHE is to get closer to its big bang; and from here, to travel less transited roads such as skeletal muscle and intestine, is to go even closer. The aim of this editorial is to expose this road for further and deeper work.

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Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure

Cited by 33 publications

References 53 publications

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

Hepatic encephalopathy: Ever closer to its big bang

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