Potential targeted therapies for the inflammatory pathogenesis of hepatic encephalopathy

Luo, Ming; Liu, Han; Hu, Shengjuan; Bai, Feihu

doi:10.1016/j.clinre.2015.06.020

Cited by 12 publications

(8 citation statements)

References 60 publications

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“…This finding is consistent with a recent fMRI study showing decreased connectivity between the right SMG and left thalamus in patients with CHE 54 . In summary, the negative correlation of FC with the level of IL-6, TNF-alpha and ammonia strengthens the role of systemic inflammation and hyperammonemia in the pathogenesis of cognitive impairment among cirrhotic patients with CHE 55 .…”

Section: Discussionmentioning

confidence: 59%

Altered cognitive control network is related to psychometric and biochemical profiles in covert hepatic encephalopathy

Tsai¹,

Wang³

et al. 2019

Sci Rep

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The cognitive control network (CCN) is a network responsible for multiple executive functions, which are impaired in covert hepatic encephalopathy (CHE). We aimed to use functional connectivity (FC) magnetic resonance imaging to test the hypothesis that CHE manifested with disconnection within the CCN, which is associated with impaired neuropsychiatric and biochemical profiles. CHE was detected with abnormally low psychometric hepatic encephalopathy scores (PHES) (total cut-off score <−4). Two seeds in the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (DLPFC) were used to calculate the FC map within the CCN. Pearson correlation analysis was performed between the CCN and psychometric, biochemical profiles including ammonia, Interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Eighteen CHE, 36 non-HE (NHE) cirrhotic patients and 36 controls were studied. Significant differences in FC were noted among groups, which revealed CHE patients had a lower FC in the bilateral lateral occipital cortex (seed in the bilateral dACC) and in the right lateral occipital and precuneus cortices (seed in the left DLPFC) (P < 0.05, corrected) compared with NHE. Progressively decreased FC in the left precentral gyrus within the CCN was noted from control, NHE to CHE. PHES positively and biochemistry negatively correlated with FC in the CCN. In conclusion, CHE patients showed aberrant FC within the CCN which is correlated with both cognitive dysfunction and biochemical profiles. Ammonia and pro-inflammatory cytokines may contribute to the occurrence of aberrant connectivity. Impaired FC within the CCN may serve as a complementary biomarker for CHE.

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Section: Discussionmentioning

confidence: 59%

Altered cognitive control network is related to psychometric and biochemical profiles in covert hepatic encephalopathy

Tsai¹,

Wang³

et al. 2019

Sci Rep

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“…Ammonia is a neurotoxin which triggers a variety of neurological complications [24] . Ammonia causes oxidative stress and brain edema [24] , [26] , [27] , induces neuroinflammation [28] , [29] , [30] , and affects vital organelles such as mitochondria [24] , [31] .…”

Section: Introductionmentioning

confidence: 99%

Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia

et al. 2016

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“…Inflammation is central to the pathogenesis of many human neurological disorders including HE. Systemic inflammation is a key player in precipitating and exacerbating HE, possibly by rendering the brain more susceptible to concurrent hyperammonemia [52]. Activated microglia also release proinflammatory mediators (e.g., cytokines TNF-α, IL-6, and IL-1β) that have also been directly linked to brain dysfunction [45].…”

Section: Discussionmentioning

confidence: 99%

Electroacupuncture Synergistically Inhibits Proinflammatory Cytokine Production and Improves Cognitive Function in Rats with Cognitive Impairment due to Hepatic Encephalopathy through p38MAPK/STAT3 and TLR4/NF-κB Signaling Pathways

Huang

Gong

Kong

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Objective. To investigate the effect of electroacupuncture (EA) on cognitive dysfunction in rats with hepatic encephalopathy and its underlying mechanism. Methods. Fifty Wistar rats were randomly divided into a normal group (n = 10) and model group (n = 40). Rat models of hepatic encephalopathy were established by administration of carbon tetrachloride and thioacetamide for a total of 12 weeks. At the 9th week after modeling, rats with cognitive impairment in the model group were identified by conducting the Morris water maze test, which were then randomly divided into a control group (CCl4) and treatment groups including EA group (CCl4 + EA), lactulose group (CCl4 + Lac), and EA plus lactulose group (CCl4 + CM), with 9 rats in each group. At the end of the 9th week, rats in CCl4 + Lac and CCl4 + CM groups had lactulose gavage at a dose of 10 mL/kg body weight, while normal control and CCl4 groups had gavage with the same volume of normal saline once a day for 21 days until the end of the experiment. Rats in CCl4 + EA and CCl4 + CM groups underwent acupuncture at Baihui (GV[DU]20), Shenting (GV[DU]24), and Zusanli (ST36) acupoints, among which EA at Baihui and Shenting acupoints were given once daily for 30 min lasting for 21 consecutive days. The effect of the treatment was measured by the Morris water maze test for learning and memory ability and magnetic resonance spectroscopy (MRS) for neuronal metabolism in the hippocampus of rats with hepatic encephalopathy. Pathological change in the rat hippocampus was observed by HE staining, while serum ammonia and liver function markers were detected. Western blot and real-time fluorescent quantitative PCR were used to detect the expressions of specific genes and proteins in the brain tissue. Results. Compared with those in the control group, rats undergoing EA had significantly shortened escape latency and increased number of platform crossing. H&E staining confirmed that EA improved brain tissue necrosis and ameliorated nuclear pyknosis in rats with hepatic encephalopathy. Significantly decreased levels of serum ammonia, alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), and total bile acid (TBA) were observed in rats undergoing EA, as well as improved levels of total protein (TP) and albumin (ALB). In addition, EA inhibited the brain expressions of TNF-α, IL-1β, IL-6, iNOS, TLR4, MyD88, NF-κB, p38MAPK, phosphorylated (p)-p38MAPK, STAT3, and p-STAT3 genes, as well as protein expressions of TNF-α, IL-6, TLR4, MyD88, NF-κB, p38MAPK, p-p38MAPK, STAT3, and p-STAT3. MRS showed increased Glx/Cr and decreased NAA/Cr, Cho/Cr and mI/Cr in the control group, and EA significantly reversed such changes in Glx/Cr and mI/Cr values. Conclusion. EA ameliorated the production of excessive proinflammatory cytokines in the hippocampus of rats with cognitive dysfunction secondary to hepatic encephalopathy, which also gave rise to subsequent changes such as reduced blood ammonia level, brain-protective activated astrocytes, and lower degree of brain tissue injury. The p38MAPK/STAT3 and TLR4/MyD88/NF-κB signaling pathways may be involved. EA can also improve the metabolism of NAA and Cho in the rat hippocampus and thereby improve learning and memory abilities.

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Potential targeted therapies for the inflammatory pathogenesis of hepatic encephalopathy

Cited by 12 publications

References 60 publications

Altered cognitive control network is related to psychometric and biochemical profiles in covert hepatic encephalopathy

Altered cognitive control network is related to psychometric and biochemical profiles in covert hepatic encephalopathy

Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia

Electroacupuncture Synergistically Inhibits Proinflammatory Cytokine Production and Improves Cognitive Function in Rats with Cognitive Impairment due to Hepatic Encephalopathy through p38MAPK/STAT3 and TLR4/NF-κB Signaling Pathways

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