Distinctive pattern of Bergmann glial pathology in human hepatic encephalopathy

Kril, Jillian J.; Flowers, Dimity; Butterworth, Roger F.

doi:10.1007/bf02815130

Cited by 20 publications

(14 citation statements)

References 18 publications

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“…This is in accordance with previous studies, since in the portacaval shunted rat model increased GFAP immunoreactivity was found in Bergmann glia, specialized cerebellar astrocytes (29), and decreased in frontal cortex (7). On the other hand, GFAP expression in Bergmann glia in human liver cirrhosis was not found to be altered, thus indicating that the course of HE affects GFAP expression (30). FIN pretreatment reduced the expression of GFAP in the hippocampus and the cortex, further suggesting its protective role on astrocytes in HE.…”

Section: Discussionsupporting

confidence: 92%

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Mladenović

Hrnčić

Petronijević

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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(HE). This study evaluated the effects of finasteride, inhibitor of neurosteroid synthesis, on motor, EEG, and cellular changes in rat brain in thioacetamide-induced HE. Male Wistar rats were divided into the following groups: 1) control; 2) thioacetamide-treated group, TAA (300 mg·kg Ϫ1 ·day Ϫ1 ); 3) finasteride-treated group, FIN (50 mg·kg Ϫ1 ·day Ϫ1 ); and 4) group treated with FIN and TAA (FIN ϩ TAA). Daily doses of TAA and FIN were administered in three subsequent days intraperitoneally, and in the FIN ϩ TAA group FIN was administered 2 h before every dose of TAA. Motor and reflex activity was determined at 0, 2, 4, 6, and 24 h, whereas EEG activity was registered about 24 h after treatment. The expressions of neuronal (NeuN), astrocytic [glial fibrilary acidic protein (GFAP)], microglial (Iba1), and oligodendrocyte (myelin oligodendrocyte glycoprotein) marker were determined 24 h after treatment. While TAA decreased all tests, FIN pretreatment (FIN ϩ TAA) significantly improved equilibrium, placement test, auditory startle, head shake reflex, motor activity, and exploratory behavior vs. the TAA group. Vital reflexes (withdrawal, grasping, righting and corneal reflex) together with mean EEG voltage were significantly higher (P Ͻ 0.01) in the FIN ϩ TAA vs. the TAA group. Hippocampal NeuN expression was significantly lower in TAA vs. control (P Ͻ 0.05). Cortical Iba1 expression was significantly higher in experimental groups vs. control (P Ͻ 0.05), whereas hippocampal GFAP expression was increased in TAA and decreased in the FIN ϩ TAA group vs. control (P Ͻ 0.05). Finasteride improves motor and EEG changes in TAA-induced HE and completely prevents the development of hepatic coma. motor tests; electroencephalography; cellular markers HEPATIC ENCEPHALOPATHY (HE) represents a clinical syndrome characterized by neurological and psychiatric disturbances that develop as a result of acute or chronic liver failure (21). Various mechanisms are involved in the pathogenesis of HE, including changes in neurotransmission (17), oxidative stress, bioenergetic failure, mitochondrial permeability transition (49), inflammatory response, and immune dysfunction (14, 52), due to accumulation of various toxins in the organism, principally ammonia (4).Changes in glutamatergic and GABAergic transmission have an important role in the development of HE (13, 16). Both acute and chronic liver failure were found to be associated with increased GABAergic activity due to increased neurosteroid synthesis. Neurosteroids are steroid compounds, synthesized in mitochondria of glial cells and neurons from cholestrol (2). Cholesterol is taken up into mitochondria via the activation of translocator protein (TSPO), a multimeric complex that spans both outer and inner mitochondrial membrane. Ammonia and manganese, toxins accumulated in HE, and proinflammatory cytokines upregulate components of TSPO and increase cholesterol uptake into the mitochondrion (2, 4). Cholesterol serves as a substrate for increased synthesis of neurosteroids, including all...

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Section: Discussionsupporting

confidence: 92%

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Mladenović

Hrnčić

Petronijević

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Exposure to lead before development of the brain revealed a lower level of expression of mRNA for GFAP. GFAP expression is also lowered by human hepatic encephalopathy (Kimura and Budka, 1986;Kril et al, 1997). Although these studies show the possibility of pathological reductions in the expression of GFAP, it remains to be determined whether depression might be associated with environmentally altered expression of GFAP.…”

Section: Discussionmentioning

confidence: 94%

Age-Dependent Reductions in the Level of Glial Fibrillary Acidic Protein in the Prefrontal Cortex in Major Depression

Miguel-Hidalgo

O'Dwyer

et al. 2004

Neuropsychopharmacol

233

125

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The density of glial cells is reduced in certain layers of the dorsolateral prefrontal cortex in major depressive disorder (MDD). Moreover, there are reductions in the packing density of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes in the same cortical layers in younger subjects with MDD. The objective of the present study was to test if the level of GFAP is preferentially decreased in younger subjects with MDD, and whether GFAP levels are correlated with the age of onset of depression. Post-mortem brain tissue punches from dorsolateral prefrontal cortex were collected from 15 subjects with MDD and 15 age-matched psychiatrically normal control subjects. Western blots were performed on gels containing duplicated samples from both subjects of each matched pair, and on gels containing samples at different ages from either the MDD or the control group. The GFAP level was calculated as the ratio of the optical density of GFAP bands to actin bands in subjects with MDD and nonpsychiatric controls. Levels of GFAP were significantly lower in subjects with MDD as compared to controls and this decrease was most prominent in subjects less than 60 years old at the time of death. In the MDD group, GFAP levels were positively correlated with age at the time of death and show a trend toward correlation with the age of onset of depression. These findings indicate that a decrease in levels of GFAP may contribute to the pathophysiology of MDD, particularly in subjects of relatively young age.

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“…While astrocytes lose their immunereactivity to GFAP, Bergmann glia in PCA rats shows an increase in GFAP immunereactivity, but in EH patients changes in GFAP immunereactivity are not detected. 5,6 Previous studies in six-month PCA rat model showed an increase in astrocyte swelling and a vacuolization in the cerebellum. 27 Additionally, microglia activation and astrocyte dysfunction were found in acute liver failure models 28 and bile duct ligated rats with hyperammonemic diet.…”

Section: Discussionmentioning

confidence: 98%

Cerebellar neurodegeneration in a new rat model of episodic hepatic encephalopathy

García‐Lezana

Oria

Romero-Giménez

et al. 2016

J Cereb Blood Flow Metab

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Hepatic encephalopathy has traditionally been considered a reversible disorder. However, recent studies suggested that repeated episodes of hepatic encephalopathy cause persistent impairment leading to neuronal loss. The aims of our study were the development of a new animal model that reproduces the course of episodic hepatic encephalopathy and the identification of neurodegeneration evidences. Rats with portacaval anastomosis underwent simulated episodes of hepatic encephalopathy, triggered by the regular administration of ammonium acetate, and/or lipopolysaccharide. The neurological status was assessed and neuronal loss stereologically quantified in motor areas. During the simulated episodes, ammonia induced reversible motor impairment in portacaval anastomosis rats. In cerebellum, stereology showed a reduction in Purkinje cell population in portacaval anastomosis and PCA+NH groups and morphological changes. An increase in astrocyte size in PCA+NH group and activated microglia in groups treated with ammonium acetate and/or lipopolysaccharide was observed. A modulation of neurodegeneration-related genes and the presence of apoptosis in Bergmann glia were observed. This new animal model reproduces the clinical course of episodic hepatic encephalopathy when ammonia is the precipitant factor and demonstrates the existence of neuronal loss in cerebellum. The persistence of over-activated microglia and reactive astrocytes could participate in the apoptosis of Bergmann glia and therefore Purkinje cell degeneration.

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Distinctive pattern of Bergmann glial pathology in human hepatic encephalopathy

Cited by 20 publications

References 18 publications

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Age-Dependent Reductions in the Level of Glial Fibrillary Acidic Protein in the Prefrontal Cortex in Major Depression

Cerebellar neurodegeneration in a new rat model of episodic hepatic encephalopathy

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