Edaravone Diminishes Free Radicals from Circulating Neutrophils in Patients with Ischemic Brain Attack

Aizawa, Hitoshi; Makita, Yoshihiro; Sumitomo, Kazuhiro; Aburakawa, Yoko; Katayama, Takayuki; Nakatani-Enomoto, Setsu; Suzuki, Yoshio; Fujiwara, Kazuhiko; Enomoto, Hiroyuki; Kuroda, Kenji; Kimura, Takashi; Yahara, Osamu; Koyama, Satoshi; Maruyama, Junichi; Nakamura, Masao; Hasebe, Naoyuki; Kikuchi, Kenjiro

doi:10.2169/internalmedicine.45.1491

Cited by 24 publications

(12 citation statements)

References 13 publications

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“…Three anti-oxidants: N-acetylcysteine (NAC), glutathione (GSH), and edaravone, were used to treat fibroblasts. All of these compounds have been widely accepted as efficient oxygen radical scavengers [34], [35], [36]. Cells pretreated with anti-oxidants and then subjected to MMC treatment for 48 hours were analyzed to determine their ROS levels via fluorescence microscopy and flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic Reticulum Stress Signaling Is Involved in Mitomycin C(MMC)-Induced Apoptosis in Human Fibroblasts via PERK Pathway

et al. 2013

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Endoplasmic reticulum (ER) stress-mediated cell apoptosis has been implicated in various cell types, including fibroblasts. Previous studies have shown that mitomycin C (MMC)-induced apoptosis occurs in fibroblasts, but the effects of MMC on ER stress-mediated apoptosis in fibroblasts have not been examined. Here, MMC-induced apoptosis in human primary fibroblasts was investigated by exposing cells to a single dose of MMC for 5 minutes. Significant inhibition of cell proliferation and increased apoptosis were observed using a cell viability assay, Annexin V/propidium iodide double staining, cell cycle analysis, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining. Upregulation of proapoptotic factors, including cleaved caspase-3 and poly ADP-ribose polymerase (PARP), was detected by Western blotting. MMC-induced apoptosis was correlated with elevation of 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP), which are hallmarks of ER stress. Three unfolded protein response (UPR) sensors (inositol-requiring enzyme 1, IRE1; activating transcription factor 6, ATF6; and PKR-like ER kinase, PERK) and their downstream signaling pathways were also activated. Knockdown of CHOP attenuated MMC-induced apoptosis by increasing the ratio of BCL-2/BAX and decreasing BIM expression, suggesting that ER stress is involved in MMC-induced fibroblast apoptosis. Interestingly, knockdown of PERK significantly decreased ER stress-mediated apoptosis by reducing the expression of CHOP, BIM and cleaved caspase-3. Reactive oxygen species (ROS) scavenging also decreased the expression of GRP78, phospho-PERK, CHOP, and BIM. These results demonstrate that MMC-induced apoptosis is triggered by ROS generation and PERK activation.

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Section: Resultsmentioning

confidence: 99%

Endoplasmic Reticulum Stress Signaling Is Involved in Mitomycin C(MMC)-Induced Apoptosis in Human Fibroblasts via PERK Pathway

et al. 2013

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“…Alternatively, more abundant cortical expression of mediators required for neutrophil extravasation (selectins, chemokines, adhesion molecules) could determine the relative predominance of cortical neutrophil accumulation. Neutrophils may promote the conversion of vulnerable yet viable cortical tissue to infarction through microvessel obstruction/thrombosis that compromises reperfusion (del Zoppo et al, 1991;Ritter et al, 2000), production of reactive oxygen species (ROS) causing oxidative stress (Aizawa et al, 2006), and release of matrix metalloproteinases that degrade components of the vascular basement membrane and extracellular matrix (Asahi et al, 2001;Gidday et al, 2005). This may account for the markedly greater BBB permeability and aggravated cerebral edema we observed in response to IL-1␤ challenge.…”

Section: Discussionmentioning

confidence: 98%

Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent Mechanisms

McColl¹,

Rothwell

Allan³

2007

J. Neurosci.

316

339

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Systemic inflammatory stimuli, such as infection, increase the risk of stroke and are associated with poorer clinical outcome. The mechanisms underlying the impact of systemic inflammatory stimuli on stroke are not well defined. We investigated the impact of systemic inflammation on experimental stroke and potential mechanisms involved. Focal cerebral ischemia was induced by intraluminal filament occlusion of the middle cerebral artery (MCAo). Brain damage and neurological deficit 24 h after MCAo were exacerbated by systemic lipopolysaccharide (LPS) administration. This exacerbation was critically dependent on interleukin (IL)-1, because coadministration of IL-1 receptor antagonist abolished the effect of LPS on brain damage. Systemic administration of IL-1 increased ischemic damage to a similar extent as LPS and also exacerbated brain edema. IL-1 markedly potentiated circulating levels of the acute phase proteins, serum amyloid A and IL-6, and the neutrophil-selective CXC chemokines, KC and macrophage inflammatory protein-2. Neutrophil mobilization and cortical neutrophil infiltration were aggravated by IL-1 before changes in ischemic damage. Neutropenia abolished the damaging effects of systemic IL-1. These data show for the first time that an acute systemic inflammatory stimulus is detrimental to outcome after experimental stroke and highlight IL-1 as a critical mediator in this paradigm. Our data suggest IL-1-induced potentiation of neutrophil mobilization via CXC chemokine induction is a putative mechanism underlying this effect. Our results may help to explain the poorer outcome in stroke patients presenting with infection and may have implications for neurodegenerative diseases involving neurovascular alterations, such as Alzheimer's disease, in which systemic inflammation can modulate disease progression.

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“…H 2 O 2 slowly induced larval muscle contraction in a dose-dependent manner (data not shown). This reaction was repressed by the prior injection of N-acetyl-L-cysteine or edaravone (37), free radical scavengers (data not shown). We then tested whether these compounds inhibit contraction caused by peptidoglycan or glucan.…”

Section: Involvement Of Ros In Muscle Contraction Induced By Bacteriamentioning

confidence: 93%

Activation of the Silkworm Cytokine by Bacterial and Fungal Cell Wall Components via a Reactive Oxygen Species-triggered Mechanism

Ishii

Hamamoto

Kamimura

et al. 2008

Journal of Biological Chemistry

100

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The insect cytokine paralytic peptide (PP) induces muscle contraction in silkworm larvae. Here we demonstrate that bacterial and fungal cell wall components peptidoglycan and glucan stimulate muscle contraction via activation of PP in the hemolymph. Anti-PP antibody suppressed the muscle contraction induced by PP, peptidoglycan, or glucan. The contraction was also inhibited by free radical scavengers and serine protease inhibitors. Moreover, injecting live silkworms with peptidoglycan or glucan generated the active form of PP. The active form of PP was also produced in vitro when peptidoglycan or glucan was incubated with hemolymph containing the PP precursor. Generation of the active form of PP was suppressed by free radical scavengers and serine protease inhibitors. Furthermore, PP activation in isolated hemolymph was inhibited by potassium cyanide, suggesting that cellular activity is involved. Stimulation by peptidoglycan promoted the generation of reactive oxygen species by silkworm hemocytes. The addition of either the active form of PP or anti-PP antibody to Staphylococcus aureus injected into silkworm larvae delayed or enhanced, respectively, the killing effect of S. aureus, suggesting that activated PP contributes to host resistance to infectious pathogens. These findings suggest that immunologic stimulants such as peptidoglycan or glucan induce reactive oxygen species production from larval hemocytes, followed by the activation of serine protease, which mediates the PP processing reaction and leads to defensive responses.

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Edaravone Diminishes Free Radicals from Circulating Neutrophils in Patients with Ischemic Brain Attack

Abstract: Objective Treatment with a free radical scavenger could be a new option for ischemic brain attack, however,

Cited by 24 publications

References 13 publications

Endoplasmic Reticulum Stress Signaling Is Involved in Mitomycin C(MMC)-Induced Apoptosis in Human Fibroblasts via PERK Pathway

Endoplasmic Reticulum Stress Signaling Is Involved in Mitomycin C(MMC)-Induced Apoptosis in Human Fibroblasts via PERK Pathway

Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent Mechanisms

Activation of the Silkworm Cytokine by Bacterial and Fungal Cell Wall Components via a Reactive Oxygen Species-triggered Mechanism

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