Edaravone Reduces Iron-Mediated Hydrocephalus and Behavioral Disorder in Rat by Activating the Nrf2/HO-1 Pathway

Zhang, Jianbo; Shi, Xia; Chen, Zhi; Geng, Junjun; Wang, Yuelong; Feng, Hua; Zhu, Gang; Chen, Qianwei

doi:10.1016/j.jstrokecerebrovasdis.2018.08.019

Cited by 16 publications

(12 citation statements)

References 28 publications

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“…The results of oxidative stress and antioxidative enzymes in the present study indicated that Eda may alleviate the severity of asthma by suppressing oxidative injury and restoring the antioxidative enzyme, SOD. It has been shown that Eda may exert a protective effect through the Nrf2/HO-1 pathway (28)(29)(30). Li et al (57) revealed that Eda protects against hyperosmolarity-induced oxidative stress and apoptosis in primary human corneal epithelial cells by increasing the expression of Nrf2 and its target genes, such as HO-1 and GPx-1.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that Eda may exert a protective effect through activation of the Nrf2/HO-1 pathway. Zhang et al (28) revealed that Eda reduced iron-mediated hydrocephalus and behavioral disorders in rats through Nrf2/HO-1 activation. In an animal model of cognitive damage induced by chronic cerebral hypoperfusion (CCH), Eda reduced CCH-induced cognitive damage and increased SOD activity and HO-1 levels, but decreased MDA levels in the hippocampus through activation of the Nrf2 pathway (29).…”

Section: Edaravone Attenuates Experimental Asthma In Mice Through Indmentioning

confidence: 99%

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Edaravone attenuates experimental asthma in mice through induction of HO‑1 and the Keap1/Nrf2 pathway

Pan

Feng

et al. 2019

Exp Ther Med

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Asthma is a chronic disease that threatens public health worldwide. Multiple studies have shown that oxidative stress plays an important role in the pathogenesis of asthma. Edaravone (Eda), a free radical scavenger, has been found to have a protective effect against lung injury due to its ability to eliminate reactive oxygen species. The present study aimed to investigate the effect of Eda on asthma and the mechanism underlying its actions. An experimental asthma model was induced in mice, before they were treated with different doses of Eda. Measurements of airway responsiveness to methacholine (Mch), cell counts and cytokine levels in bronchoalveolar lavage fluid (BALF) and of the oxidative products and antioxidant enzymes in lung tissue were taken in these asthma model mice and compared with control mice. Protein levels of kelch-like ECH-associated protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were determined in the lung tissue of normal mice and Nrf2 and HO-1-deficient mice subject to the asthma model to investigate the mechanisms underlying Eda action. The results indicated that Eda effectively reduced airway responsiveness to Mch. The total number of cells and the numbers of eosinophils, lymphocytes and neutrophils in BALF of asthma model mice were also significantly reduced by Eda treatment when compared with normal saline treatment. Eda treatment significantly alleviated perivascular edema, peribronchial inflammation and macrophage infiltration in the alveolar space and decreased the levels of inflammatory cytokines released in BALF compared with control. Eda also significantly reduced the levels of oxidative stress markers in BALF and restored the levels of antioxidative enzyme, superoxide dismutase, when compared with control. The Keap1/Nrf2 ratio was significantly decreased with Eda compared with control due to an increase in Nrf2 and a decrease in Keap1 expression. HO-1 expression was increased by Eda. The airway responsiveness of Nrf2-/mice or HO-1-/mice to Mch was significantly higher compared with normal mice treated with Eda. Taken together, the results of the present study show that Eda exerts anti-inflammatory and antioxidative effects, which suggests a potential use for Eda in reduction of asthma severity. The activated Keap1/Nrf2 pathway and HO-1 may be involved in the anti-asthmatic effect of Eda.

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Section: Discussionmentioning

confidence: 99%

Section: Edaravone Attenuates Experimental Asthma In Mice Through Indmentioning

confidence: 99%

Edaravone attenuates experimental asthma in mice through induction of HO‑1 and the Keap1/Nrf2 pathway

Pan

Feng

et al. 2019

Exp Ther Med

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“…Nrf2 is a transcription factor involved in endogenous antioxidant cell protection. Nrf2 can mediate the expression of phase II detoxifying enzymes and antioxidant genes through the actions of antioxidant-response elements (AREs) (24), such as HO-1, which is a Nrf2 target gene (25). We found that Ori treatments up-regulated the mRNA expression of Nrf2 and HO-1, which subsequently led to an increase in the GSH content, as well as the activity of GPX, GR and catalase in the liver.…”

Section: Discussionmentioning

confidence: 95%

Oridonin Attenuates the Effects of Chronic Alcohol Consumption Inducing Oxidative, Glycative and Inflammatory Injury in the Mouse Liver

Yan

Huang

Mong

et al. 2021

In Vivo

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Background/Aim: Oridonin (Ori) is a diterpenoid naturally present in medicinal plants with a potential as an antioxidant agent. This study aimed to evaluate the hepatic antioxidative, anti-glycative and anti-inflammatory properties of Ori at 0.125 and 0.25% against chronic ethanol intake in mice. Materials and Methods: Mice were divided into five groups: i) normal diet group, ii) Ori group, iii) ethanol diet (Lieber-DeCarli liquid diet with ethanol) group, iv) ethanol diet plus 0.125% Ori and v) ethanol diet plus 0.25% Ori. After 8 weeks of Ori supplementation, blood and liver tissue were used for analyses. Results: Ethanol increased the production of reactive oxygen species and nitric oxide, decreased glutathione content, and lowered the activity of glutathione peroxide, glutathione reductase and catalase. Ethanol suppressed the hepatic mRNA expression of nuclear factor E2-related factor 2. Ori supplements reversed these changes. Ethanol increased hepatic N e -(carboxyethymethyl)-lysine (CML) and pentosidine levels, and enhanced aldose reductase (AR) activity and mRNA expression. Ori supplements at only 0.25% decreased CML and pentosidine levels, and lowered the AR activity as well as its mRNA expression. Ethanol increased the hepatic release of tumor necrosis factor-alpha, transforming growth factor-beta1, interleukin (IL)-1beta and IL-6. Histological data showed that ethanol induced necrosis and inflammatory cell infiltration, while Ori supplements alleviated these inflammatory responses. Ethanol up-regulated the hepatic mRNA expression of nuclear factor kappa B, myeloperoxidase and p38. Ori supplements reversed these changes. Conclusions: These novel findings suggest that Ori could be used as a potent agent against alcohol-induced hepatotoxicity.Alcohol abuse is a worldwide public health issue because it causes high prevalence of alcoholic liver disorders (1). The typical pathological characteristics of alcoholic hepatotoxicity due to excessive and chronic ethanol intake include oxidative, glycative and inflammatory injury (2, 3). Ethanol and its major metabolite, acetaldehyde, promote hepatic cytochrome P4502E1 (CYP2E1) activity and impair the nuclear factor E2-related factor 2 (Nrf2)-associated antioxidant system (4). These events subsequently lead to the overproduction of reactive oxygen species (ROS) and nitric oxide (NO), and deplete glutathione (GSH) in liver, which finally increase hepatic oxidative stress (5). In addition, acetaldehyde can react with N-ethyl amino groups to form advanced glycation end-products (AGEs) (6). AGEs, such as N e -(carboxyethymethyl)-lysine (CML), N-ethyllysine or pentosidine, have been detected in the liver of patients with alcoholic hepatic diseases (7). A key enzyme, aldose reductase (AR), responsible for AGEs formation has been shown to be up-regulated in alcoholic liver disease (8).At the same time, ethanol activates nuclear factor kappa B (NF-ĸB) and mitogen-activated protein kinase (MAPK) pathways, which result in the release of down-stream inflammatory mediators and ...

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“…The expression of genes involved in the Nrf2 pathway was upregulated following edaravone treatment in TDP-43-expressing 1464R cells in the presence of ethacrynic acid. It was previously shown that edaravone activates the Nrf2/HO-1 pathway, exerts neuroprotective effects (including a reduction of neurological and cognitive dysfunction), and protects against cell apoptosis in mouse and rat models of various neurological disorders [ 39 , 40 , 41 , 42 ]. In the Nrf2/G93A mouse model of ALS pathology, the expression of Nrf2 was accelerated in both spinal cord motor neurons and lower limb muscles during disease progression [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of Edaravone on TDP-43 Plus Oxidative Stress-Induced Neurotoxicity in Neuronal Cells: Analysis of Its Neuroprotective Mechanisms Using RNA Sequencing

Soejima-Kusunoki¹,

Okada²,

Saito³

et al. 2022

Pharmaceuticals

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Edaravone is a free-radical scavenger drug that was recently approved for the treatment of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. A pathological hallmark of ALS is the accumulation of ubiquitinated or phosphorylated aggregates of the 43-kDa transactive response DNA binding protein (TDP-43) within the cytoplasm of motor neurons. This study revealed the efficacy of edaravone in preventing neuronal cell death in a TDP-43 proteinopathy model and analyzed the molecular changes associated with the neuroprotection. The viability of the neuronal cells expressing TDP-43 was reduced by oxidative stress, and edaravone (≥10 μmol/L) protected in a concentration-dependent manner against the neurotoxic insult. Differential gene expression analysis revealed changes among pathways related to nuclear erythroid 2-related-factor (Nrf2)-mediated oxidative stress response in cells expressing TDP-43. In edaravone-treated cells expressing TDP-43, significant changes in gene expression were also identified among Nrf2-oxidative response, unfolded protein response, and autophagy pathways. In addition, the expression of genes belonging to phosphatidylinositol metabolism pathways was modified. These findings suggest that the neuroprotective effect of edaravone involves the prevention of TDP-43 misfolding and enhanced clearance of pathological TDP-43 in TDP-43 proteinopathy.

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Edaravone Reduces Iron-Mediated Hydrocephalus and Behavioral Disorder in Rat by Activating the Nrf2/HO-1 Pathway

Cited by 16 publications

References 28 publications

Edaravone attenuates experimental asthma in mice through induction of HO‑1 and the Keap1/Nrf2 pathway

Edaravone attenuates experimental asthma in mice through induction of HO‑1 and the Keap1/Nrf2 pathway

Oridonin Attenuates the Effects of Chronic Alcohol Consumption Inducing Oxidative, Glycative and Inflammatory Injury in the Mouse Liver

The Protective Effect of Edaravone on TDP-43 Plus Oxidative Stress-Induced Neurotoxicity in Neuronal Cells: Analysis of Its Neuroprotective Mechanisms Using RNA Sequencing

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