Novel effects of edaravone on human brain microvascular endothelial cells revealed by a proteomic approach

Onodera, Hidetaka; Arito, Mitsumi; Sato, Toshiyuki; Ito, Hidemichi; Hashimoto, Tsuyoshi; Tanaka, Yuichiro; Kurokawa, Manae S.; Okamoto, Ken‐ichi; Suematsu, Naoya; Kato, Tomohiro

doi:10.1016/j.brainres.2013.08.019

Cited by 12 publications

(9 citation statements)

References 33 publications

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“…Moreover, we also demonstrated that edaravone treatment alone tightened the brain endothelial barrier. Our data expand and further support previous observations on barrier enhancing effect of edaravone [35], [36].…”

Section: Discussionsupporting

confidence: 92%

“…Edaravone treatment alone increased the metabolic activity and impedance of the endothelial layers. A beneficial effect of edaravone on human endothelial cells was also found previously by resistance measurement and proteomic assay [35], [36]. The edaravone concentrations used were in the millimolar range similarly to another independent work on cultured human brain endothelial cells.…”

Section: Discussionsupporting

confidence: 77%

“…To further reveal the mechanism of protection, brain microvessels [33] and the blood-brain barrier [34] were investigated as potential pharmaceutical targets of edaravone in animal models of stroke. The effect of edaravone alone has been described on barrier function: it promoted tight junction formation via activation of sphingosin-1-phospate signaling pathway [35] and down-regulation of interleukin-1β induced monocyte chemoattractant protein-1 secretion [36] in human microvascular endothelial cells. In a recent study, methylglyoxal-induced decrease in cell viability and methylglyoxal enhanced cell injury by oxygen-glucose deprivation were alleviated by pretreatment with edaravone in brain endothelial cells [37].…”

Section: Introductionmentioning

confidence: 99%

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Edaravone Protects against Methylglyoxal-Induced Barrier Damage in Human Brain Endothelial Cells

et al. 2014

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BackgroundElevated level of reactive carbonyl species, such as methylglyoxal, triggers carbonyl stress and activates a series of inflammatory responses leading to accelerated vascular damage. Edaravone is the active substance of a Japanese medicine, which aids neurological recovery following acute brain ischemia and subsequent cerebral infarction. Our aim was to test whether edaravone can exert a protective effect on the barrier properties of human brain endothelial cells (hCMEC/D3 cell line) treated with methylglyoxal.MethodologyCell viability was monitored in real-time by impedance-based cell electronic sensing. The barrier function of the monolayer was characterized by measurement of resistance and flux of permeability markers, and visualized by immunohistochemistry for claudin-5 and β-catenin. Cell morphology was also examined by holographic phase imaging.Principal FindingsMethylglyoxal exerted a time- and dose-dependent toxicity on cultured human brain endothelial cells: a concentration of 600 µM resulted in about 50% toxicity, significantly reduced the integrity and increased the permeability of the barrier. The cell morphology also changed dramatically: the area of cells decreased, their optical height significantly increased. Edaravone (3 mM) provided a complete protection against the toxic effect of methylglyoxal. Co-administration of edaravone restored cell viability, barrier integrity and functions of brain endothelial cells. Similar protection was obtained by the well-known antiglycating molecule, aminoguanidine, our reference compound.ConclusionThese results indicate for the first time that edaravone is protective in carbonyl stress induced barrier damage. Our data may contribute to the development of compounds to treat brain endothelial dysfunction in carbonyl stress related diseases.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Edaravone Protects against Methylglyoxal-Induced Barrier Damage in Human Brain Endothelial Cells

et al. 2014

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“…These data confirm our previous results on the protective and antioxidant effects of edaravone on cultured brain endothelial cells [23]. Edaravone promoted tight junction formation in vascular endothelial cells [52] and exerted antioxidant effects during NMDA excitotoxicity on brain slices [53]. The protective effect of edaravone was also demonstrated Fig.…”

Section: Discussionsupporting

confidence: 91%

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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“…Edaravone (3-methyl-1-phenyl-pyrazolin-5-one) is a novel free radical scavenger and brain protectant, which could inhibit both the nonenzymatic lipid peroxidation and lipoxygenase pathways arachidonate cascade reactions, and has a potent antioxidant activity (Hironaka et al, 2011). Thus, edaravone has several protective effects against ischemia-reperfusion-induced damage, including vascular endothelial cell injury (Onodera et al, 2013), delayed neuronal death (Jiao et al, 2011), brain edema (Zhou et al, 2009), infarct (Okamura et al, 2014) and concomitant neurological deficits. Following a multicenter, placebo-controlled and double-blind clinic trial, edaravone has been commercialized for the treatment of acute ischaemic stroke (Yoshino and Kimura, 2006).…”

Section: Introductionmentioning

confidence: 99%

Study on the interaction of plasma protein binding rate between edaravone and taurine in human plasma based on HPLC analysis coupled with ultrafiltration technique

Tang

et al. 2014

Biomedical Chromatography

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In this work, two high-performance liquid chromatography (HPLC) assays were developed and validated for the independent determination of edaravone and taurine using 3-methyl-1-p-tolyl-5-pyrazolone and L-glutamine as internal standards. In in vitro experiments, human plasma was separately spiked with a mixture of edaravone and taurine, edaravone or taurine alone. Plasma was precipitated with acetonitrile containing 0.1% formic acid. Ultrafiltration was employed to obtain the unbound ingredients of the two drugs. The factors that might influence the ultrafiltration effiency were elaborately optimized. Plasma supernatant and ultrafiltrate containing taurine were derivated with o-phthalaldehyde and ethanethiol in the presence of 40 mmol/L sodium borate buffer (pH 10.2) at room temperature within 1 min. Chromatographic separations were achieved on an InertSustain C18 column (250 × 4.6 mm, 5 µm). Isocratic 50 mmol/L ammonium acetate-acetonitrile and gradient 50 mmol/L sodium acetate (pH 5.3)-methanol were respectively selected as the mobile phase for the determination of edaravone and taurine. All of the validation data including linearity, extraction recovery, precision, accuracy and stability conformed to the requirements. Results showed that there were no significant alterations in the plasma protein binding rate of taurine and edaravone, implying that the proposed combination therapy was pharmacologically feasible.

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Novel effects of edaravone on human brain microvascular endothelial cells revealed by a proteomic approach

Cited by 12 publications

References 33 publications

Edaravone Protects against Methylglyoxal-Induced Barrier Damage in Human Brain Endothelial Cells

Edaravone Protects against Methylglyoxal-Induced Barrier Damage in Human Brain Endothelial Cells

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

Study on the interaction of plasma protein binding rate between edaravone and taurine in human plasma based on HPLC analysis coupled with ultrafiltration technique

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