Artesunate restores spatial learning of rats with hepatic encephalopathy by inhibiting ammonia-induced oxidative damage in neurons and dysfunction of glutamate signaling in astroglial cells

Wu, Yuanyuan; Zhang, Li; Li, Wenting; Yang, Yi; Zhao, Jiangming

doi:10.1016/j.biopha.2016.09.104

Cited by 16 publications

(10 citation statements)

References 29 publications

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“…The effect of artesunate on the CNS of rats with HE has been tested too. Rats administered with artesunate (50 or 100 mg/kg), significantly improved its spatial learning ability in the Morris water maze test, while in vitro, cerebellar granule neurons treated with artesunate (100 μM) significantly reduced its glutamate release, as well as the Na + K + -ATPase activity, indicating that artesunate has a neuroprotective effect, although the effect over astrocytes was not evaluated in this work [100]. Additional evidence about the effect of artesunate over glial cells is lacking, but this drug has a relevant role in the field of the HE treatment choices.…”

Section: Novel Pharmacological Findings Over He Treatmentmentioning

confidence: 84%

Astrocyte Pathophysiology in Liver Disease

Pérez‐Monter¹,

Torre-Delgadillo²

2018

Astrocyte - Physiology and Pathology

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Liver disease is one of the major chronic disabilities around the world. It is known that global casualties are increasing because of virus C infection, alcohol consumption, or nonalcoholic circumstances. One of the main derived comorbidities of liver disease is the hepatic encephalopathy (HE), a severe neuropsychological syndrome derived from the acute or chronic liver disease. A key feature accounting for HE symptoms in cirrhotic patients is brain edema, which is triggered by hyperammonemia. In basal conditions, ammonia can be metabolized in the central nervous system (CNS) by astrocytes, which synthetize glutamine using ammonia and glutamate as substrates. In hyperammonemic conditions, astrocytes synthetize large amounts of glutamine generating a hyperosmotic condition, inducing these cells to become swollen in shape, invoking the characteristic symptom clinically manifested in patients with HE, as brain edema; this condition is regulated by water channels called aquaporins (AQPs) and by other molecules such as myoinositol. Experimental evidence suggests that some small non-coding RNAs may regulate AQPs expression both in vivo an in vitro and that some pharmacological interventions improve cognitive impairment in cirrhotic patients. It is undeniable that astrocytes and the different signaling pathways beneath its plasma membrane play a crucial role in liver disease-derived HE and represent some of the novel pharmacological targets to treat comorbidities of the liver disease.

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Section: Novel Pharmacological Findings Over He Treatmentmentioning

confidence: 84%

Astrocyte Pathophysiology in Liver Disease

Pérez‐Monter¹,

Torre-Delgadillo²

2018

Astrocyte - Physiology and Pathology

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“…ARS has been found to induce ROS production and accumulation in different cancer cell lines, including the generation of O 2 − (Greenshields et al, ; Li et al, ; Roh et al, ; Wu, Zhang, Li, Yang, & Zhao, ; Yang et al, ). In contrast, ARS‐induced ROS production in control normal cells appears to be dependent on the cell type, once elevated ROS content was verified in certain kinds of cells whereas reduction or no alteration was observed in other cell types (Beccafico et al, ; Cheng et al, ).…”

Section: Discussionmentioning

confidence: 99%

Markers of oxidative‐nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes

Mota

Garcia

Bonfim

et al. 2019

J of Applied Toxicology

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Artesunate (ARS) is a semi‐synthetic derivative of artemisinin, used as an outstanding antimalarial drug, which also displays antitumor, anti‐inflammatory and immunosuppressive effects. In spite of the numerous reports showing the antitumor activity of ARS, the particular mechanisms associated with its cytotoxicity and genotoxicity in non‐neoplastic human cells remain unclear. Here we aimed to verify the specific chromosome damages and the changes in markers of oxidative‐nitrosative stress and apoptosis triggered by ARS exposure in human peripheral blood lymphocytes. Cultures were incubated in the presence of ARS and the number of binucleated cells was determined. To discriminate between micronuclei (MN) containing a whole chromosome or an acentric chromosome, the MN test was employed in combination with the fluorescence in situ hybridization assay. Alterations in the levels of superoxide anion (O2−) and nitric oxide (NO) were measured by the nitroblue tetrazolium and Griess assay, respectively. Changes in the expression of the apoptotic markers were assessed by immunocytochemistry. We found that ARS induced a significant formation of both centromere‐positive MN (C+ MN) and centromere‐negative MN (C– MN). These alterations were accompanied by an increase in both cellular levels of O2− and total NO production, and a remarkable enhancement in the expression of the apoptotic markers cytochrome c and caspases 8 and 9. Together these findings reveal that ARS induces changes in the oxidative‐nitrosative status of human lymphocytes, which are followed by apoptosis and clastogenic and aneugenic effects.

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“…However, the parkin remarkably reduced in ACC. In addition, oxidative stress had been activated in the brains of human patients and/or in animal models of HE, which damaged the mitochondria physiological function (Mousa et al, ; Wu et al, ). When mitochondria depolarized, Pink1 (a mitochondrial Ser/Thr kinase) accumulated on the OMM, and recruited Parkin (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Changes of Mitochondria in Substantia Nigra and Anterior Cerebral Cortex of Hepatic Encephalopathy Induced by Thioacetamide

Bai

Wang

et al. 2019

The Anatomical Record

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Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from chronic or acute liver failure. Under the condition of HE, various factors such as reactive oxygen species, inflammatory factors, ammonia poisoning and amino acids alteration lead to changes of mitochondria. Selective depletion of damaged mitochondrion is essential for maintaining the morphology and function of mitochondria and cells. In this study, molecular biology analysis was used to analyze the mitochondrial morphology in the substantia nigra (SN) and anterior cerebral cortex (ACC) of the HE mice. The results revealed that the drp1, mfn1 and mfn2 increased in mRNA level of SN, which indicated the changes of mitochondrial morphology in HE mice. The drp1 and mfn2 genes were up‐regulated, then, the Opa1 exhibited no significant change in the ACC of HE mice. Further study demonstrated that the mitochondrial autophagy related genes, pink1 and parkin, increased in SN, while the parkin reduced in ACC of HE mice. In addition, uncoupling protein (ucp2) increased in mRNA level of SN and ACC, and the ucp4 had no change or reduced in SN and ACC, respectively. These findings suggested that the mitochondrial dynamics is different in the SN and ACC of HE mice. Therefore, our results indicated that mitochondrial dynamics provided a potential treatment strategy for HE through the fission, fusion and autophagy of genes. Anat Rec, 302:1169–1177, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

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Artesunate restores spatial learning of rats with hepatic encephalopathy by inhibiting ammonia-induced oxidative damage in neurons and dysfunction of glutamate signaling in astroglial cells

Cited by 16 publications

References 29 publications

Astrocyte Pathophysiology in Liver Disease

Astrocyte Pathophysiology in Liver Disease

Markers of oxidative‐nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes

The Changes of Mitochondria in Substantia Nigra and Anterior Cerebral Cortex of Hepatic Encephalopathy Induced by Thioacetamide

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