The neurogliovascular unit in hepatic encephalopathy

Claeys, Wouter; Hoecke, Lien Van; Lefere, Sander; Geerts, Anja; Verhelst, Xavier; Vlierberghe, Hans Van; Degroote, Helena; Devisscher, Lindsey; Vandenbroucke, Roosmarijn E.; Steenkiste, Christophe Van

doi:10.1016/j.jhepr.2021.100352

Cited by 29 publications

(22 citation statements)

References 152 publications

(505 reference statements)

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“…The (CNS)inflammatory milieu postulated for ME/CFS may be doubly linked to another central observation in ME/CFS, namely, metabolic, and especially mitochondrial (and possibly peroxisomal) ( Che et al, 2022 ) dysfunction. As noted in minimal hepatic encephalopathy, even small increases in abnormal metabolites (like ammonia) can have profound effects on astrocyte and microglial function, especially in concert with inflammatory signals ( Stewart and Smith, 2007 ; Jaeger et al, 2019 ; Claeys et al, 2021 ). It is therefore plausible that metabolic alterations and/or oxidative and nitrosative stress in ME/CFS lead to glial dysfunction ( Cobb and Cole, 2015 ; Morris et al, 2017 ; Paul et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Renz‐Polster

Tremblay

Bienzle

et al. 2022

Front. Cell. Neurosci.

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Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.

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Section: Discussionmentioning

confidence: 99%

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Renz‐Polster

Tremblay

Bienzle

et al. 2022

Front. Cell. Neurosci.

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“…15 The ammonia stimulates both astrocytes and microglia and triggers inflammatory responses due to the synthesis of proinflammatory cytokines and oxidative stress, leading to neurotoxicity. 16,17 Interestingly, serum ATX levels in cirrhotic patients with hepatic encephalopathy were higher than in patients without encephalopathy, 18 and the involvement of the ATX-LPA pathway within the brain in the pathogenesis of HE remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Ammonia, reactive oxygen species (ROS) or NOS, and proinflammatory cytokines interact synergistically in acute HE characterized by astrocyte swelling/brain edema . The ammonia stimulates both astrocytes and microglia and triggers inflammatory responses due to the synthesis of proinflammatory cytokines and oxidative stress, leading to neurotoxicity. , …”

Section: Introductionmentioning

confidence: 99%

Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy

Roy

Chakrabarti

Dasgupta

et al. 2022

ACS Chem. Neurosci.

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Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin−lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1β (interleukin-1β), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1β, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH 4 CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.

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“…При микроскопическом исследовании головного мозга из обеих исследованных групп наблюдались изменения нейронов, клеток глии, мелких церебральных сосудов и нейропиля, что свидетельствовало о комплексном характере поражения вещества мозга при рассматриваемых заболеваниях [2,[5][6][7]17]. Вместе с тем проведённое исследование показало, что наблюдаемые изменения обнаруживали определённые различия в зависимости от этиологии процесса.…”

Section: Discussionunclassified

“…Проведённое исследование показало, что в основе морфологической картины поражения головного мозга при алкогольном и HCV-ассоциированном циррозе печени лежат патологические изменения глио-ангионейронального комплекса, которые имели некоторые различия в зависимости от типа основного заболевания печени. Наиболее яркие из них касались проявлений глиальной реакции, которая является характерным морфологическим признаком ПЭ [2,16,17]. Показано, что при циррозе алкогольной этиологии в мозге преобладали продуктивные изменения астроцитов, включая появление множественных альцгеймеровских астроцитов II типа, а также спонгиоформные изменения в сером и белом веществе.…”

Section: заключениеunclassified

Morphological changes in the brain in liver cirrhosis of alcoholic and viral etiology

Maybogin

Nedzvedz

Kornev³

2022

Acta biomedica scientifica

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Background. Hepatic encephalopathy is an actual problem of modern medicine. However, its pathogenesis and histological picture are currently insufficiently studied. Less is known about the impact of the nature of primary liver disease on pathogenesis and histological picture of hepatic encephalopathy. This determines the relevance of further morphological studies of the brain in the late stages of liver cirrhosis of various etiologies.The aim. To establish and compare the morphological changes in the brain in alcoholic liver cirrhosis and viral (hepatitis C virus (HCV)) cirrhosis.Materials and methods. The morphological study of the brain of 40 deceased in outcome of HCV-associated cirrhosis and 23 patients died in outcome of chronic alcoholism was carried out. Histological changes in various parts of the brain were studied using survey and elective stains. The immunohistochemical study of HCV NS3 and CD68 expression in different brain regions was performed in cases of HCV-infection.Results. The changes of neurons, glial cells and cerebral microvessels underlie in the basis of morphological picture of brain damage in both studied groups underlie that corresponds to the “classical” model of hepatic encephalopathy pathogenesis. At the same time, a number of morphological features were observed. The most prominent differences concerned the manifestations of the glial reaction. The productive changes of macroglial cells with the appearance of multiple Alzheimer’s astrocytes type 2 as well as spongious changes in subcortical white matter dominated in the observations of alcoholic cirrhosis. In contrast, microglia cells reaction (microgliosis) in white matter was noticed in HCV-associated cirrhosis.Conclusions. The differences in histological signs of brain in the terminal stages of liver disease of viral and alcoholic etiology are shown. They broaden current idea of morphological picture of hepatic encephalopathy, and may be used to study its pathogenesis.

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The neurogliovascular unit in hepatic encephalopathy

Cited by 29 publications

References 152 publications

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy

Morphological changes in the brain in liver cirrhosis of alcoholic and viral etiology

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