Protective role of chrysin on thioacetamide-induced hepatic encephalopathy in rats

El-Marasy, Salma A.; Awdan, Sally A. El; Abd‐Elsalam, Reham M.

doi:10.1016/j.cbi.2018.11.021

Cited by 65 publications

(37 citation statements)

References 62 publications

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“…The discrimination between F and N was measured by comparing the exploration time of F with that of N. DI (discrimination index) expressed the proportion of the exploration times of the two objects. DI was then calculated; DI = N-F/N, similar to previously published [22].…”

Section: Methodsmentioning

confidence: 99%

Ambrosin, a potent NF-κβ inhibitor, ameliorates lipopolysaccharide induced memory impairment, comparison to curcumin

et al. 2019

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Despite its poor bioavailability, curcumin is a promising natural polyphenol targeting NF-κβ. NF-κβ is a target for new therapeutics because it plays a pivotal role in the pathophysiology of Alzheimer disease (AD). In contrast, ambrsoin, a sesquiterpene lactone which is a potent NF-κβ inhibitor, is scarcely studied in AD models. The current work aims to assess the efficacy of ambrosin as a possible remedy for AD. In silico studies showed that bioavailability and BBB permeability could be favorable for ambrosin over curcumin. Memory impairment was induced in mice by single intraperitoneal injection of LPS (0.4 mg/kg). Treated groups received curcumin (100 mg/kg) or ambrosin at doses (5 or 10 mg/kg) for 7 days. Mice in treated groups showed a significant improvement in memory functions during Morris water maze and object recognition tests. Curcumin and ambrosin (10 mg/kg) inhibited the upsurge of NF-κβp65 transcript and protein levels. Consequently, downstream pro-inflammatory and nitrosative mediators were inhibited, namely, TNF-α, IL-1β, COX-2 and iNOS. BACE1 was inhibited, thereby reducing amyloid plaques (Aβ) deposition and eventually reducing inflammation and apoptosis of neurons as revealed by immunohistopathological examination. In conclusion, ambrosin can be repurposed as AD remedy after further pharmacokinetic/pharamacodynamic assessments. It could serve as an additional lead drug for AD therapeutics.

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Section: Methodsmentioning

confidence: 99%

Ambrosin, a potent NF-κβ inhibitor, ameliorates lipopolysaccharide induced memory impairment, comparison to curcumin

et al. 2019

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“…Increased brain ammonia levels and neuroinflammation are also present in rats with thioacetamide (TAA)‐induced liver injury, associated with reduced scores in the novel object recognition task . Chrysin, a natural flavonoid with anti‐inflammatory properties, improved thioacetamide‐induced motor incoordination and cognitive deficits and attenuated hyperammonaemia and neuroinflammation …”

Section: Animal Models Of Mhe and Chronic Hyperammonaemia Also Show Nmentioning

confidence: 99%

“…47 Chrysin, a natural flavonoid with antiinflammatory properties, improved thioacetamide-induced motor incoordination and cognitive deficits and attenuated hyperammonaemia and neuroinflammation. 48 Rats with TAA-induced acute liver failure show increased CCL2 (also known as MCP-1) expression and microglia activation in the cerebral cortex and CCL2 receptors inhibition improves neurological score and reduces cortical microglia activation. 49 In in vitro studies, TNF-α treatment induces CCL2 release by neurons and contributes to microglia activation which may contribute to neurological decline in HE.…”

Section: Infiltration Of Lymphocytes In Meningesmentioning

confidence: 99%

Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications

et al. 2019

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Several million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonaemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is because of the changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations. We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss. We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function. Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze. These alterations are reversed by treatments that reduce peripheral inflammation (anti‐TNFα, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP). The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.

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“…Studies in animal models of hyperammonemia and MHE have shown that the emergence of neurological alterations is mediated by the induction of neuroinflammation, which alters glutamatergic and GABAergic neurotransmission, leading to cognitive and motor impairment [5][6][7][8][9][10][11][12][13][14][15]. Both in patients and in animal models, the cerebellum seems to be the first brain area to be affected in early stages of chronic liver diseases [6,[16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway

Balzano

Arenas

Dadsetan

et al. 2020

J Neuroinflammation

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Background: Patients with liver cirrhosis may develop hepatic encephalopathy. Rats with chronic hyperammonemia exhibit neurological alterations mediated by peripheral inflammation and neuroinflammation. Motor incoordination is due to increased TNF-a levels and activation of its receptor TNFR1 in the cerebellum. The aims were to assess (a) whether peripheral inflammation is responsible for TNF-a induction in hyperammonemic rats, (b) the cell type(s) in which TNF-a is increased, (c) whether this increase is associated with increased nuclear NF-κB and TNFR1 activation, (d) the time course of TNF-a induction, and (e) if TNF-a is induced in the Purkinje neurons of patients who die with liver cirrhosis. Methods:We analyzed the level of TNF-a mRNA and NF-κB in microglia, astrocytes, and Purkinje neurons in the cerebellum after 1, 2, and 4 weeks of hyperammonemia. We assessed whether preventing peripheral inflammation by administering an anti-TNF-a antibody prevents TNF-a induction. We tested whether TNF-a induction is reversed by R7050, which inhibits the TNFR1-NF-κB pathway, in ex vivo cerebellar slices. Results: Hyperammonemia induced microglial and astrocyte activation at 1 week. This was followed by TNF-a induction in both glial cell types at 2 weeks and in Purkinje neurons at 4 weeks. The level of TNF-a mRNA increased in parallel with the TNF-a protein level, indicating that TNF-a was synthesized in Purkinje cells. This increase was associated with increased NF-κB nuclear translocation. The nuclear translocation of NF-κB and the increase in TNF-a were reversed by R7050, indicating that they were mediated by the activation of TNFR1. Preventing peripheral inflammation with an anti-TNF-a antibody prevents TNF-a induction. Conclusion: Sustained (4 weeks) but not short-term hyperammonemia induces TNF-a in Purkinje neurons in rats. This is mediated by peripheral inflammation. TNF-a is also increased in the Purkinje neurons of patients who die with liver cirrhosis. The results suggest that hyperammonemia induces TNF-a in glial cells and that TNF-a released by glial cells activates TNFR1 in Purkinje neurons, leading to NF-κB nuclear translocation and the induction of TNF-a expression, which may contribute to the neurological alterations observed in hyperammonemia and hepatic encephalopathy.

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Protective role of chrysin on thioacetamide-induced hepatic encephalopathy in rats

Cited by 65 publications

References 62 publications

Ambrosin, a potent NF-κβ inhibitor, ameliorates lipopolysaccharide induced memory impairment, comparison to curcumin

Ambrosin, a potent NF-κβ inhibitor, ameliorates lipopolysaccharide induced memory impairment, comparison to curcumin

Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications

Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway

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