Chapter 22: Hepatic encephalopathy: a disorder in glial-neuronal communication

doi:10.1016/S0079-6123(08)61756-2

Progress in Brain Research

Volume 94, 1992, Pages 261-269

https://doi.org/10.1016/S0079-6123(08)61756-2 Get rights and content

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The chapter discusses recent progress, concerning the role of astrocytes in hepatic encephalopathy (HE). New concepts regarding the role of second messengers (cyclic AMP and Ca2+) and protein phosphorylation are discussed. Data on glycogen metabolism that are especially pertinent to a potential defect in glial-neuronal communication is presented. Finally, discussion on derangements in cytoskeletal proteins, volume regulation, and the involvement of the peripheral type benzodiazepine receptor is given. HE occurs in two clinical forms: acute or fulminant hepatic failure (FHF) and chronic (portal-systemic encephalopathy, PSE). FHF, generally occurring in the setting of viral or toxic hepatitis, usually presents with the rapid onset of delirium, coma, and seizures. PSE on the other hand, manifests initially with subtle personality changes, confusion, episodic stupor, and when severe with coma.

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Hyperammonemia in Hepatic Encephalopathy
2018, Journal of Clinical and Experimental Hepatology
Citation Excerpt :
Astrocytes are also involved in synapse formation during development, as well as in their maintenance in adults.105 Further, astrocytic dysfunction in CHE has been postulated to also to largely contribute to the neurobehavioral abnormalities associated with CHE.106–111 Among their many biological roles, astrocytes are also important for neuronal development, synaptic transmission, homeostasis, and neuroprotection.105
The precise mechanism underlying the neurotoxicity of Hepatic Encephalopathy (HE) is remains unclear. The dominant view has been that gut-derived nitrogenous toxins are not extracted by the diseased liver and thereby enter the brain. Among the various toxins proposed, the case for ammonia is most compelling. Events that lead to increased levels of blood or brain ammonia have been shown to worsen HE, whereas reducing blood ammonia levels alleviates HE. Clinical, pathological, and biochemical changes observed in HE can be reproduced by increasing blood or brain ammonia levels in experimental animals, while exposure of cultured astrocytes to ammonium salts reproduces the morphological and biochemical findings observed in HE. However, factors other than ammonia have recently been proposed to be involved in the development of HE, including cytokines and other blood and brain immune factors. Moreover, recent studies have questioned the critical role of ammonia in the pathogenesis of HE since blood ammonia levels do not always correlate with the level/severity of encephalopathy. This review summarizes the vital role of ammonia in the pathogenesis of HE in humans, as well as in experimental models of acute and chronic liver failure. It further emphasizes recent advances in the molecular mechanisms involved in the progression of neurological complications that occur in acute and chronic liver failure.
Reactive Nitrogen and Oxygen Species in Hepatic Encephalopathy
2017, Liver Pathophysiology: Therapies and Antioxidants
Oxidative and nitrosative stresses derived from hepatic encephalopathy (HE), the most important complication during liver disease, play a determinant role in its pathophysiology. Experimental models in animals and postmortem studies in humans have widely characterized a range of biochemical alterations associated with oxidative/nitrosative stress triggered by ammonia, manganese, and proinflammatory cytokines. This chapter is aimed to gather evidence of experimental protocols carried out to characterize the mechanisms by which these factors, by themselves, in combination, or through their relation with other pathological processes, such as N-methyl-D-aspartate (NMDA) receptor activation, inflammation, and nitric oxide production, provoke the characteristic oxidative/nitrosative stress in HE. Identification of reliable markers of damage and elucidation of the level at which the generation of reactive species occurs could provide therapeutic targets for the development of alternative pharmacologic treatments for HE in the future.
Neuroinflammation in hepatic encephalopathy: Mechanistic aspects
2015, Journal of Clinical and Experimental Hepatology
Hepatic encephalopathy (HE) is a major neurological complication of severe liver disease that presents in acute and chronic forms. While elevated brain ammonia level is known to be a major etiological factor in this disorder, recent studies have shown a significant role of neuroinflammation in the pathogenesis of both acute and chronic HE. This review summarizes the involvement of ammonia in the activation of microglia, as well as the means by which ammonia triggers inflammatory responses in these cells. Additionally, the role of ammonia in stimulating inflammatory events in brain endothelial cells (ECs), likely through the activation of the toll-like receptor-4 and the associated production of cytokines, as well as the stimulation of various inflammatory factors in ECs and in astrocytes, are discussed. This review also summarizes the inflammatory mechanisms by which activation of ECs and microglia impact on astrocytes leading to their dysfunction, ultimately contributing to astrocyte swelling/brain edema in acute HE. The role of microglial activation and its contribution to the progression of neurobehavioral abnormalities in chronic HE are also briefly presented. We posit that a better understanding of the inflammatory events associated with acute and chronic HE will uncover novel therapeutic targets useful in the treatment of patients afflicted with HE.
The role of glia in stress: Polyamines and brain disorders
2014, Psychiatric Clinics of North America
Citation Excerpt :
Failure of synaptic transmission64,65 and vasodilation66,67 has been ascribed to the malfunction of perisynaptic and perivascular astrocytes, respectively. Neuronal damage is evident after glial depletion in hepatic encephalopathy,68 and neuronal degeneration can occur after apoptosis of glial cells.69 It has long been accepted that glia provide a support function to neurons by buffering extracellular K+ and glutamate.70–74
Role of cerebral endothelial cells in the astrocyte swelling and brain edema associated with acute hepatic encephalopathy
2012, Neuroscience
Citation Excerpt :
All animal procedures followed guidelines established by the National Institute of Health Guide for the Care and Use of Laboratory Animals and were approved by our Institutional Animal Care and Use Committee (IACUC). The use of ammonia-treated cultured astrocytes as a model for hepatic encephalopathy is highly appropriate since substantial evidence invokes the role of ammonia in the pathogenesis of hepatic encephalopathy (Albrecht and Jones, 1999; Hazell and Butterworth, 1999), and astrocytes are the principal cells affected in this condition (Norenberg, 1981, 1998; Norenberg et al., 1992). Moreover, many of the findings occurring in hepatic encephalopathy in vivo are also observed in these cultures, including characteristic morphologic changes, cell swelling, defects in glutamate transport, up-regulation of the peripheral benzodiazepine receptor (recently renamed the 18-kDa translocator protein), reduction in levels of GFAP and myo-inositol, disturbance in energy metabolism, and evidence of oxidative/nitrosative stress (for review, see Norenberg et al., 2009).
Brain edema is an important complication of acute hepatic encephalopathy (AHE), and astrocyte swelling is largely responsible for its development. Elevated blood and brain ammonia levels have been considered as major etiological factors in this edema. In addition to ammonia, recent studies have suggested that systemic infection, inflammation (and associated cytokines (CKs)), as well as endotoxin (lipopolysaccharide (LPS)) are also involved in AHE-associated brain edema. As endothelial cells (ECs) are the first resident brain cells exposed to blood-borne “noxious agents” (i.e., ammonia, CKs, LPS) that are present in AHE, these cells may be in a critical position to react to these agents and trigger a process resulting in astrocyte swelling/brain edema. We therefore examined the effect of conditioned media (CM) from ammonia, LPS and cytokine-treated cultured brain ECs on cell swelling in cultured astrocytes. CM from ammonia-treated ECs when added to astrocytes caused significant cell swelling, and such swelling was potentiated when astrocytes were exposed to CM from ECs treated with a combination of ammonia, LPS and CKs. We also found an additive effect when astrocytes were exposed to ammonia along with CM from ammonia-treated ECs. Additionally, ECs treated with ammonia showed a significant increase in the production of oxy-radicals, nitric oxide (NO), as well as evidence of oxidative/nitrative stress and activation of the transcription factor nuclear factor kappa B (NF-κB). CM derived from ECs treated with ammonia, along with antioxidants (AOs) or the NF-κB inhibitor BAY 11-7082, when added to astrocytes resulted in a significant reduction in cell swelling, as compared to the effect of CM from ECs-treated only with ammonia. We also identified increased nuclear NF-κB expression in rat brain cortical ECs in the thioacetamide (TAA) model of AHE. These studies suggest that ECs significantly contribute to the astrocyte swelling/brain edema in AHE, likely as a consequence of oxidative/nitrative stress and activation of NF-κB.
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Chapter 22: Hepatic encephalopathy: a disorder in glial-neuronal communication

Publisher Summary

Diazepam binding inhibitor: a neuropeptide located in selected neuronal populations of rat brain

Science

Intracellular Ca2+ potentiates Na+/H+ exchange and cell differentiation induced by phorbol ester in U937 cells

Eur. J. Biochem.

The peripheral-type benzodiazepine receptor: localization to the mitochondrial outer membrane

J. Biol. Chem.

Ca/calmodulin-dependent protein kinase activity in primary astrocyte cultures

Glia

Experimental hepatic encephalopathy: changes in the binding of gammaaminobutyric acid

Science

Flunitrazepam binding to intact and homogenized astrocytes and neurons in primary cultures

J. Neurochem.

Pharmacological evidence that the non-neuronal diazepam binding site in primary cultures of glial cells is associated with a calcium channel

Eur. J. Pharmacol.

Octadecaneuropeptide (ODN; anxiety peptide) displaces diazepam more potently from astrocytic than from neuronal binding sites

Eur. J. Pharmacol.

Role of calcium-dependent protein kinases in astrocytic cell volume regulation

Trans. Am. Soc. Neurochem.

Controlled trial of dexamethasone and mannitol for the cerebral edema of fulminant hepatic failure

Gut

Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions. 1. Neurons and glia

J. Electron Microsc. Techn.

Phosphorylation of keratin and vimentin polypeptides in normal and transformed mitotic human epithelial amnion cells: behavior of keratin and vimentin filaments during mitosis

J. Cell Biol.

Mediation of cell volume regulation by Ca2+ influx through stretch-activated channels

Nature

Biochemistry and physiology of brain ammonia

Physiol. Rev.

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JAMA

The effect of ammonia on astrocyte glycogen content

Trans. Am. Soc. Neurochem.

The action of ammonia on astrocyte glycogen levels

Trans. Am. Soc. Neurochem.

Effect of ammonium chloride on the astrocyte benzodiazepine receptor

Brain Res.

Effect of phenol on the astrocyte benzodiazepine receptor

Trans. Am. Soc. Neurochem.

Hepatic encephalopathy and cerebral edema

Sem. Liver Dis.

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J. Membr. Biol.

An alteration in the phosphorylation of vimentin-type intermediate filaments is associated with mitosis in cultured mammalian cells

Cell

Activity of ion channels during volume regulation by clonal NIE115 neuroblastoma cells

Proc. Natl. Acad. Sci. U.S.A.

Ammonia-induced swelling of rat cerebral cortical slices: implications for the pathogenesis of brain edema in acute hepatic failure

Metab. Brain Dis.

Cyclic AMP-modulated phosphorylation of intermediate filament proteins in cultured avian myogenic cells

Mol. Cell. Biol.

Increased peripheral benzodiazepine binding sites following portacaval anastomosis in the rat

Soc. Neurosci. Abstr.

The role of brain capillaries in the pathogenesis of hepatic encephalopathy

Hepatology

A common mechanism for activation of the Na+/H+ exchanger by different types of stimuli

FASEB J.

Morphologic effects of ammonia on primary astrocyte cultures. I. Light microscopic studies

J. Neuropathol. Exp. Neurol.

Morphologic effects of ammonia on primary astrocyte cultures. II. Electron microscopic studies

J. Neuropathol. Exp. Neurol.

Effect of cyclic AMP on ammonia-induced alterations in primary astrocyte cultures

J. Neuropathol. Exp. Neurol.

A correlated histochemical and quantitative study on cerebral glycogen after brain injury in the rat

Exp. Neurol.

Glial fibrillary acidic protein and S-100 protein in human hepatic encephalopathy: immunocytochemical demonstration of dissociation of two glia-associated proteins

Acta Neuropathol. (Berl.)

Cell volume regulation in epithelia with emphasis on the role of osmolytes and the cytoskeleton

A method using 3–0-methyl-D-glucose and phloretin for the determination of intracellular water space of cells in monolayer culture

Anal. Biochem.