How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?

Watanabe, Kazutoshi; Tanaka, Masahiko; Yuki, Satoshi; Hirai, Manabu; Yamamoto, Yorihiro

doi:10.3164/jcbn.17-62

Cited by 158 publications

(139 citation statements)

References 106 publications

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“…Mean ± SEM, n = 4, ANOVA, Bonferroni test, *p < 0.05 compared to the control group; # p < 0.05 compared to the kainate-treated group in kainate-induced epilepsy models in rats [24,54]. All these preclinical data support the BBB protective effects of edaravone which may contribute to its efficacy in the clinical treatment of acute stroke and amyotrophic lateral sclerosis [17].…”

Section: Discussionmentioning

confidence: 53%

“…The importance of the BBB as a therapeutic target is increasingly recognized and several anti-inflammatory or antioxidant drugs and novel molecules were identified as BBB protective on culture models [25] and introduced in the therapy of disease like stroke, amyotrophic lateral sclerosis and epilepsy [15][16][17]. We demonstrated that simvastatin protected brain endothelial cells in the Fig.…”

Section: Discussionmentioning

confidence: 77%

“…Simvastatin is a lipophilic statin exerting neuroprotective effects [21], which also protects the BBB in an acute stroke model in rats [22]. Edaravone is an excellent free radical scavenger molecule, which is clinically used for treating acute stroke and amyotrophic lateral sclerosis [17]. Our group demonstrated the protective effect of edaravone on brain endothelial cells against methylglyoxal-induced barrier damage [23].…”

Section: Introductionmentioning

confidence: 89%

“…Taking into account the central role of the BBB in central nervous system (CNS) physiology [12] and neuropathologies [13] the cerebral vasculature emerges as a therapeutic target for neurological diseases [14,15]. Vascular inflammation and oxidative stress are central pathways in many CNS diseases such as stroke, amyotrophic lateral sclerosis and epilepsy, and anti-inflammatory or antioxidant drugs are also used to treat them [15][16][17]. For the present study we selected three clinically used drugs, the anti-inflammatory simvastatin and dexamethasone, and the free radical scavenger edaravone.…”

Section: Introductionmentioning

confidence: 99%

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Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Barna

Walter

Harazin

et al. 2020

Fluids Barriers CNS

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Background: Excitotoxicity is a central pathological pathway in many neurological diseases with blood-brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes.Methods: Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR.Results: Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment. Conclusion:Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Barna

Walter

Harazin

et al. 2020

Fluids Barriers CNS

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“…The σ S -response high-activity cell subpopulation may be considered a novel therapeutic target for potential inhibition of cipro-induced mutagenesis to antibiotic cross resistance. We show that the drug edaravone, an ROS scavenger indicated for human use in ALS in the U.S. and cerebral infarction in Japan (Miyaji et al, 2015; Watanabe et al, 2018), inhibits cipro induction of mutagenesis but not its antibiotic (killing) activity. Edaravone, at concentrations seen in new formulations (100μM) (Corporation, 2014; Li et al, 2012; Parikh et al, 2016), inhibited the appearance of σ S -high cells (Figure 3C), accumulation of σ S -fusion protein (Figure S3F), appearance of ROS-high cells (Figure 3D), and most (82% ± 1% of) RifR mutagenesis (Figure 3E).…”

Section: Resultsmentioning

confidence: 93%

Gamblers: an Antibiotic-induced Evolvable Cell Subpopulation Differentiated by Reactive-oxygen-induced General Stress Response

Pribis¹,

Garcı́a-Villada²,

Zhen³

et al. 2018

Preprint

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32Antibiotics can induce mutations that cause antibiotic resistance. Yet, despite their importance, 33 mechanisms of antibiotic-promoted mutagenesis remain elusive. We report that the 34 fluoroquinolone antibiotic ciprofloxacin (cipro) induces mutations that cause drug resistance by 35 triggering differentiation of a mutant-generating cell subpopulation, using reactive oxygen species 36 (ROS) to signal the sigma-S (σ S ) general-stress response. Cipro-generated DNA breaks activate 37 the SOS DNA-damage response and error-prone DNA polymerases in all cells. However, 38 mutagenesis is restricted to a cell subpopulation in which electron transfer and SOS induce ROS, 39 which activate the σ S response, allowing mutagenesis during DNA-break repair. When sorted, 40 this small σ S -response-"on" subpopulation produces most antibiotic cross-resistant mutants. An 41FDA-approved drug prevents σ S induction specifically inhibiting antibiotic-promoted mutagenesis. 42 Furthermore, SOS-inhibited cell division, causing multi-chromosome cells, is required for 43 mutagenesis. The data support a model in which within-cell chromosome cooperation together 44 with development of a "gambler" cell subpopulation promote resistance evolution without risking 45 most cells. 46 47 48 49 51 break repair, reactive oxygen species (ROS), RpoS (σ S ) stress response, SOS response, 52 starvation stress response, stress-induced mutagenesis, transient differentiation 53 54 100 once antibiotics have gone (Lewis, 2010). Persister formation can occur stochastically, leaving 101 populations ready for a stress that they have not encountered (Balaban et al., 2004), and can also 102 be induced responsively via stress-response regulons including the SOS- (Dorr et al., 2009) and 103 σ S -response (Radzikowski et al., 2016) regulons. It is unknown whether antibiotics induce 104 4 transient differentiation that could promote resistance through mutagenesis, e.g., (Frenoy and 105 Bonhoeffer, 2018). 106Here we show that low, sub-inhibitory doses of cipro induce transient differentiation of a 107 small cell subpopulation with high ROS and σ S -response activity, that generates mutants, 108 including cross-resistant mutants: a "gambler" subpopulation. We show that the ROS promote 109 mutagenesis in gamblers by activating the σ S response, which allows mutagenic repair of cipro-110 triggered DSBs-a novel signaling/differentiating role of ROS in mutagenesis. We elaborate the 111 regulatory chain from cipro to ROS to σ S response to mutant production, and also discover a 112 requirement for SOS-induced inhibition of cell division, causing multiple chromosomes per cell. 113Mathematical analysis supports a model in which multiple chromosomes allow sharing of cellular 114 resources (e.g., recombination, complementation), avoiding deleterious consequences of some 115 mutations during mutagenesis and repair. Thus, multiple chromosomes allow higher mutation 116 rates to be maintained -resulting in faster adaptation. The findings imply a highly regulated, novel 117 transie...

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Cerebral Malaria and Neuronal Implications of Plasmodium Falciparum Infection: From Mechanisms to Advanced Models

2022

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Reorganization of host red blood cells by the malaria parasite Plasmodium falciparum enables their sequestration via attachment to the microvasculature. This artificially increases the dwelling time of the infected red blood cells within inner organs such as the brain, which can lead to cerebral malaria. Cerebral malaria is the deadliest complication patients infected with P. falciparum can experience and still remains a major public health concern despite effective antimalarial therapies. Here, the current understanding of the effect of P. falciparum cytoadherence and their secreted proteins on structural features of the human blood-brain barrier and their involvement in the pathogenesis of cerebral malaria are highlighted. Advanced 2D and 3D in vitro models are further assessed to study this devastating interaction between parasite and host. A better understanding of the molecular mechanisms leading to neuronal and cognitive deficits in cerebral malaria will be pivotal in devising new strategies to treat and prevent blood-brain barrier dysfunction and subsequent neurological damage in patients with cerebral malaria. MalariaMalaria is an ancient mosquito-borne disease caused by protozoan parasites of the genus Plasmodium. According to the latest World Malaria Report published by the World Health

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How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?

Cited by 158 publications

References 106 publications

Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Gamblers: an Antibiotic-induced Evolvable Cell Subpopulation Differentiated by Reactive-oxygen-induced General Stress Response

Cerebral Malaria and Neuronal Implications of Plasmodium Falciparum Infection: From Mechanisms to Advanced Models

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