Just Accepted by International Journal of Neuroscience

Edaravone’s Free Radical Scavenging Mechanisms of Neuroprotection Against Cerebral Ischemia: Review of the Literature Yanxin Ren, Bing Wei, Xirui Song, Nan An, Yiying Zhou, Xinxin Jin, Yuyang Zhang doi:10.3109/00207454.2014.959121

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Abstract Free radicals and oxidative stress play key roles in cerebral ischemic pathogenesis and represent pharmacological targets for treatment. Edaravone (Edv), one of antioxidant agents that have been used in acute ischemic stroke in both clinical settings and animal experiments, exerts neuroprotective effect on ischemic injured brains. This review is aimed to elaborate the latest molecular mechanisms of the neuroprotection of Edv on cerebral ischemia and provide reasonable evidence in its clinical application. It is found that Edv has neuroprotective influence on cerebral ischemia, which is closely related to the facets of scavenging reactive oxygen species (ROS), hydroxyl radical (•OH) and reactive nitrogen species (RNS). And it is a good antioxidant agent that can be safely used in the treatment of cerebral ischemia and chronic neurodegenerative disorders as well as other ischemia/reperfusion (I/R)-related diseases. The combination of Edv with thrombolytic therapy also can be applied in clinical settings and will be greatly beneficial to patients with stroke.

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Yanxin Ren, Bing Wei, Xirui Song, Nan An, Yiying Zhou, Xinxin Jin Yuyang Zhang* School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China

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Correspondence is addressed to Dr. Yuyang Zhang Yuyang Zhang, Ph.D.

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Professor of Pharmacology

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Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China, 110016

Abstract

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Tel: +86 24 23986261 or 23986303; Cell phone: +86 24 13614053862; E-mail: [email protected]

Free radicals and oxidative stress play key roles in cerebral ischemic pathogenesis and represent pharmacological targets for

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Edaravone’s Free Radical Scavenging Mechanisms of Neuroprotection Against Cerebral Ischemia: Review of the Literature

treatment. Edaravone (Edv), one of antioxidant agents that have been used in acute ischemic stroke in both clinical settings and animal experiments, exerts neuroprotective effect on ischemic injured brains. This review is aimed to elaborate the

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clinical application. It is found that Edv has neuroprotective influence on cerebral ischemia, which is closely related to the facets of scavenging reactive oxygen species (ROS), hydroxyl radical (•OH) and reactive nitrogen species (RNS). And it is a

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good antioxidant agent that can be safely used in the treatment of cerebral ischemia and chronic neurodegenerative disorders as well as other ischemia/reperfusion (I/R)-related diseases. The combination of Edv with thrombolytic therapy also can be

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applied in clinical settings and will be greatly beneficial to patients with stroke.

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Key words: edaravone; free radicals; oxidative stress; cerebral ischemia; neuroprotection

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Abbreviations

arachidonate

AA

Alzheimer's disease

AD

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latest molecular mechanisms of the neuroprotection of Edv on cerebral ischemia and provide reasonable evidence in its

acute hemorrhagic stroke

AHS

amyotrophic lateral sclerosis

ALS

2

BCAO

catalase

CAT

cerebral blood flow

CBF

central nervous systems

CNS

dihydroethidium

DHE

Edaravone

Edv

ESR

endothelial nitric-oxide synthase

glutathione reductase glutathione

ST

Electron spin resonance

glutamate

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bilateral carotid artery occlusion

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BBB

C

blood-brain barrier

AC

AIS

eNOS GLU

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acute ischemic stroke

GR GSH

3

GST

glucose-6-phosphate dehydrogenase

G6PDH

hydrogen peroxide

H2O2

hydroxyl radical

•OH

inducible nitric-oxide synthase

iNOS

internal carotid artery occlusion

ICAO

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glutathione-S-transferase

AC

C

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GSH-Px

ischemia/reperfusion

I/R

KO

middle cerebral artery occlusion malondialdehyde

ST

knock-out

MCAO MDA

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glutathione peroxidase

matrix metalloproteinases

MMPs

Multiple free radical scavenging

MULTIS

4

NIHSS

nitric oxide

NO

NO synthase

NOS

Parkinson's disease

PD

peroxynitrite

ONOO–

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National Institutes of Health Stroke Scale

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NMDA

C

N-methyl-D-aspartate

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NGF

recombinant tPA

rtPA

RNS

ST

reactive nitrogen species reactive oxygen species

ROS

traumatic brain injury

TBI

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nerve growth factor

transient hypoxia-ischemia

tHI

singlet oxygen

1

O2

5

sAD

single electron transfer

SET

superoxide dismutase

SOD

tumor necrosis factor alpha

TNF-a

tissue plasminogen activator

tPA

uric acid

UA

4-hydroxynonenal 7-nitroindozale

VSMC

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vascular smooth muscle cell wild-type

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sporadic Alzheimer's disease

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OPB

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2-oxo-3-(phenylhydrazono)-butanoic acid

AC

O2•−

WT 4-HNE

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superoxide anion

7-NI

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Stroke is a life-threatening disease causing high mortality and morbidity worldwide. Statistics from data of 187 countries showed that stroke and ischemic heart disease collectively killed 12.9 million people in 2010

[1]

. In the past two decades,

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death rate caused by stroke has been increasing. Therefore, it is in need of the exploration of potent drugs for the treatment of stroke.

[2]

, the detrimental role of the free radicals in ischemic brain had been extensively

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cells of central nervous systems(CNS)

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Since Eugene et al first reported that cerebral ischemia might initiate a series of pathological free radical reactions in the

discussed. Once the ischemia of brain tissues occurs, energy generation is suppressed, then intracellular and extracellular

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electrolyte are imbalanced, and thus free radical production via enzymatic and nonenzymatic pathways is activated in the ischemic brains. The free radicals are cytotoxic molecules that play important roles in the pathogenesis of cerebral ischemia. They induce further damages to neuronal cells, resulting in the development of cerebral cytotoxic edema and infarction [3].

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Introduction

Therefore, protecting neuronal cells from free radical attacks has been considered to be an important therapeutic target in the acute phase of stroke.

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been exploited to provide effective neuroprotection in animals[4,5] and patients with acute ischemic stroke (AIS) in clinical settings as well. These patients had low scores of National Institutes of Health Stroke Scale (NIHSS) after Edv treatment [6].

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Watanabe et al confirmed that Edv was a potent anti-ischemia agent and its mechanism might closely be associated with the beneficial antioxidant activities and the inhibition of cerebral arachidonate (AA) cascade[4,5]. Lapchak devoted to a critical

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review on clinical efficacy and toxicology of the drug published from 1993 – 2008. It was finally concluded that Edv was a

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useful neuroprotective agent and should be further pursued worldwide as a candidate for development [7]. Neuroprotective effects of Edv on cerebral ischemia have been reported[8,9], including those on suppression of free radical

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damages and neuronal cell death, decrease of edema and infarct size. It also increases the expression of nerve growth factor (NGF), an essential factor for neuronal growth, improves the survival of human astrocytes subjected to hypoxia/reoxygenation and thus has a neurotrophic effect on the therapy of brain injury

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Edv (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, Fig.1), also known as MCI-186 approved in Japan in 2001, has

[8,9]

. It is well known that Edv

scavenges free radicals and inhibits pro-inflammatory responses in patients and animals with ischemia [6,10]. It suppresses the progress of infarcts and edema in patients with severe internal carotid artery occlusion (ICAO) and therefore decreases

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cortical infarct volume in rats with transient focal ischemia [12].

Experiments and clinical applications show that Edv, as an antioxidant, is as effective as melatonin that is known a natural

neuroprotectants that prevent brain tissues from damage

[13]

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neurohomone synthesized and secreted in the pineal gland, on suppressing oxidative stress, thus it is one of promising . Results of quantitative determination with electron spin

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resonance (ESR) spin trapping-based multiple free radical scavenging (MULTIS) method indicated that Edv had a high

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efficacy in free radical scavenging activity. It was as potent as other known natural antioxidants such as uric acid (UA), glutathione (GSH) and trolox. It possesses relatively high scavenging abilities for a variety of free radicals but with low

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specificity for a specific free radical [14]. UA was a powerful antioxidant and showed a neuroprotective effect in the study of animals with focal brain ischemia[15], but its prognostic value in human has been controversial [16,17] , which might make the clinical application of the drug obscure in the long run. NXY-059, another antioxidant, not fortunate as Edv, might have

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mortality on acute stage [11]. It also significantly improves neurological outcome and decreases total volume as well as

been expected to be in clinical application to cerebral ischemia, but has not been used in fact

[18]

. A large scale study of

Phase III revealed that it was not better than placebo in the treatment of patients with acute stroke though histological

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was not only considered as an effective neuroprotectant but also a better candidate for the treatment of acute noncardioembolic ischemic stroke compared with other free radical scavengers like sodium ozagrel

[21]

. In addition, the

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application of Edv, according to the cost-effectiveness analysis, can directly reduce medical cost as well as nursing care cost from the socioeconomic point of view. In this paper, the recent progresses of the potential and precise molecular

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mechanisms of Edv’s scavenging reactive oxygen species (ROS) against cerebral ischemia are reviewed.

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1. ROS scavenging

ROS such as superoxide anion (O2•−), hydrogen peroxide (H2O2) and singlet oxygen (1O2), the products of biochemical and

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physiological reactions in I/R, are known to initiate the signaling pathways of cell death and damage nucleic acids, proteins and lipids [22,23]. The DNA oxidation can cause mutations and changes in gene expression. Mitochondrial DNA seems more sensitive to the mutations due to lack of DNA repair enzymes in the site. Furthermore, the oxidation of proteins may lead to

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damage was reduced and behavioral outcome was improved by the drug used in animal stroke model [19,20]. In contrast, Edv

the formation of insoluble protein aggregation which causes pathological neurodegenerative changes, lipid oxidation and further damage to neuronal cell membranes, resulting in development of cerebral edema. The enhanced ROS generation in

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dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) existed in relatively low concentrations in the brain. The administration of Edv could effectively reduce the ROS generation in both animals and human beings with cerebral I/R [6]

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. The potential mechanisms of the action may involve in the following aspects.

1.1. Suppression of O2•− production

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Studies in male Balb/c mice subjected to permanent middle cerebral artery occlusion (MCAO) show that the O2•−production,

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also as a source of hydroxyl radical (•OH), increased 1h after the onset of the ischemia in ischemic core of the brain, and then the same occurred in the boundary area of the infarct zone between 3 and 6 h. Immunostaining revealed that most of

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O2•− were aggregated in neurons [24]. Other experiments also found that superoxide, the primary ROS and its derivatives had caused the breakdown of blood-brain barrier (BBB) and mediated damages to cell structures in ischemic animals [25]. Recent studies evaluated the temporal and spatial profiles of O2•− on the acute stage of permanent focal cerebral ischemia in

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cerebral ischemia could not easily been antagonized by anti-oxidative systems, because the enzymes including superoxide

mice through an in situ staining technique with dihydroethidium (DHE). Results revealed that Edv pretreatment suppressed O2•− increase in the ischemic core. Tissue damages were significantly ameliorated and infarct volume in the infarct rim was

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1.2 Suppression of 1O2 production

In the process of cerebral ischemia, H2O2 reacts with hypochloride (HOCl) catalyzed by myeloperoxidase (MPO) to form O2 [Fig.2]. The cultured cerebellar granule neurons treated with O2•− or 1O2 die with characteristics of apoptotic death,

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which indicates that 1O2 is an inducer of the neuronal damage [26]. Yoko Nishinaka et al reported that 1O2 was released from

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the infiltrated neutrophils during I/R injury and caused inflammatory responses and cell death [27].

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Protective effects of Edv on neuronal damage induced by 1O2 have been examined in rat neuronal B50 cell line irradiated by 525 nm green light in rose Bengal solution. Fluorospectrometry and mitochondrial respiration assay revealed that Edv at a

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concentration range of 100 to 400 µM suppressed concentration-dependently the 1O2 production and attenuated the cell death [27]. In addition, results from confocal microscopy and time-lapse imaging also showed that the drug prevented membrane damages and suppressed cell death induced by 1O2. After ischemia, the infiltration of neutrophils into the

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reduced, compared with the control [24].

ischemic brain tissues was observed. Edv suppressed 1O2 release from the activated human neutrophils with an IC50 of approximate 0.3 µM and protected the brain tissues from acute infarct damage, which indicated that Edv was a potent 1O2

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1.3 Up-regulation of antioxidative enzymes

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When the oxidative stress occurred in the ischemic brain, the rapid overproduction of free radicals overwhelms the detoxification and scavenging capacity of cellular antioxidative enzymes like SOD, CAT, GSH-Px, and non-enzymatic

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antioxidants such as vitamin E, vitamin C and GSH, resulting in a severe and immediate damage to neurons [29]. A crucial

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enzyme in ROS scavenging pathway is SOD that transforms the highly reactive O2•− into H2O2 and molecular oxygen [Fig.2]. Jiao et al reported that Edv did not only markedly decrease the levels of malondialdehyde (MDA), a well

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established indicator of oxidative stress in cells and tissues, and increase SOD level, but also notably alleviate the delayed neuronal death and cognitive dysfunction of hippocampus after focal cerebral ischemia. Moreover, it reduced MDA level greatly and raised SOD activity when it was administrated upon reoxygenation after I/R injury in cultured hippocampal cells

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scavenger [28].

in a dose-dependent manner compared with the control [30].

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GSH-Px, and as a result O2•− is turned into nontoxic water and oxygen

[22,23]

. The antioxidative enzymes are, therefore,

considered to play an important role in ROS detoxification [Fig.2]. The fact that free radical scavengers exert

from various aspects

[29]

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neuroprotective effects and improve the expression of the antioxidant enzymes during cerebral I/R has been demonstrated . Edv enhances the activity of SOD so as to lead more effective dismutation of superoxide radical

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anions. In contrast, it can raise the activity of other antioxidative enzymes including CAT and GSH-Px, which helps

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decrease the accumulation of H2O2 produced via the reaction catalyzed by SOD. Therefore, the overproduced H2O2 built up by the raised SOD could be finally detoxified [Fig.2]. What’s more, a high level of GSH-Px possesses greater protection

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from oxidative stress than either SOD or CAT alone. It was reported that the level of GSH-Px was decreased after ischemic insult. For the purpose of investigating the effect of Edv on brains after cerebral I/R injury, a bilateral carotid artery occlusion (BCAO) for 85-min followed by a 45-min reperfusion was conducted in aged rats. I/R injury resulted in the

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SOD catalyzes O2•− to produce H2O2 which can be detoxified by endogenous antioxidative enzymes including CAT and

reduction of GSH-Px level and the increase of protein carbonyl content. Edv treatment significantly suppressed all these changes and neuronal damages via inhibiting oxidative stress [31]. Neurological examination and the evaluation of cognitive

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ameliorated neurological and histological outcome by elevating endogenous antioxidative status as well as suppressing apoptotic responses in rats with MCAO. Edv treatment significantly increased the activity of the antioxidative enzymes

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including GSH-Px, glutathione reductase (GR), glutathione-S-transferase (GST) and Glucose-6-phosphate dehydrogenase (G6PDH), as well as CAT, in striatum zone of rats with focal cerebral ischemia when compared with the control group [34].

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2. •OH scavenging

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The high levels of H2O2 generated in ROS system and •OH generated following H2O2 through the Fenton reaction (H2O2+ Fe2+ →•OH + Fe3+ + –OH) jointly induce extensive DNA damage, ATP depletion, and severe neurotoxicity in ischemia brain . The presence of •OH results in the oxidation of unsaturated fatty acids in cellular membrane, which leads to cell injury

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[22]

and the disturbance of brain function. Lipid peroxidation in membranes generated toxic aldehydes such as 4-hydroxynonenal (4-HNE), which damaged a variety of ion channels, transporters, and cytoskeletal proteins [22].

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function are important indices for drug therapy in the recuperative course of the experimental brain ischemia [32,33]. Edv also

Evidence supports that Edv is an excellent scavenger for •OH, which is considered to be the basis of protection from cerebral ischemia [10]. Edv has been found to have promising activity as an oxidative radical scavenger, quenching and

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lipid-soluble peroxyl radical-induced peroxidation, which were different from the inhibitory effects of vitamins C and E [35]. Edv Treatment (3 and 10 mg/kg, i.v.) alleviated ischemia-induced impairment in a dose-related manner, and suppressed the

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post-ischemic increase of •OH in the hippocampus of BCAO/reperfusion rats [24]. Edv in its anionic form has been predicted to react 8.6 times faster than its neutral form. It usually presents in the anionic form under the physiological pH, and the

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mechanism of single electron transfer (SET) has been found to be the most contribution to overall reactivity with •OH,

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closely followed by radical adduct formation[36]. Edv and its derivatives are excellent free radical scavengers and can transfer one electron via SET mechanism under the physiological condition, then form a stable oxidation product

3. RNS scavenging

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2-oxo-3-(phenylhydrazono)-butanoic acid (OPB) through a radical intermediate [37,38] [Fig.2].

RNS including nitric oxide (NO) and peroxynitrite (ONOO–) play a big part in the process of cerebral I/R injury.

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inhibiting both •OH–dependent and •OH–independent lipid peroxidation. It had inhibitory effects on both water-soluble and

Superoxide can react with NO to produce ONOO–, a potent oxidant that causes the irreversible inhibition of mitochondria respiration and inflict serious damage on mitochondrial components, and then lead to disruption of BBB and exacerbate

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injury and other diseases of CNS [40,41]. It is synthesized under the catalysis of nitric-oxide synthase (NOS) which contains three isoforms, endothelial nitric-oxide synthase (eNOS), inducible nitric-oxide synthase (iNOS) and neuronal nitric-oxide

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synthase (nNOS). NO formed under the catalysis of eNOS may increase cerebral vasodilation that is beneficial to blood circulation, inhibit platelet aggregation and adhesion, and there are extra benefits. It also acts as a neurotransmitter or

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neuromodulator [42]. On the other hand, up-regulated NO level catalyzed by iNOS during inflammation or by nNOS in brain

neurodegeneration and cell apoptosis [Fig.3]

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3.1 Up-regulation of eNOS

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and some other tissues may react with the superoxide to produce ONOO– which will evoke nitrative stress that causes

It is known that eNOS plays an important role in neuroprotection so as to benefit to the post-ischemic revascularization greatly, for instance, it promotes endothelial cell proliferation and migration, angiogenesis and arterial-venous

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brain damages [Fig.3] [39]. NO exerts dual roles of neuroprotection and neurotoxicity in the pathophysiology of cerebral I/R

differentiation as well [43]. NO produced under the catalysis of eNOS has beneficial effects on the maintenance of vascular homeostasis and the protection of brain cells from the ischemic injury [Fig.3].

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substances and enzymes mediating cell death and apoptosis via ROS pathways are investigated in the duration of cerebral I/R injury. Transgenic and gene-knockout animals provide a necessary condition for basic research and clinical practice in

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the study area [44]. Cui et al used adult wild-type (WT) and eNOS-knockout (KO) mice subjected to transient (2.5h) MCAO were used to investigate the role of eNOS after stroke. Decreased arteriogenesis was remarkable in the KO mice compared

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with the WT ones, as demonstrated by reduction of proliferation of vascular smooth muscle cells (VSMC), arterial density

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and diameter in ischemic brains [45]. Gertz et al also demonstrated that there were protective effects on angiogenesis which were completely abolished when animals were treated with an eNOS inhibitor in MCAO mice [46]. The data indicates that

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eNOS not only promotes vascular dilation but also increases VSMC proliferation and migration, and thereby enhances arteriogenesis after stroke. Experiments conducted by Otani and Togashi illustrate that Edv can inhibit the oxidation, increase the eNOS expression, enhance the NO production, improve and conserve the cerebral blood flow (CBF) and

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Transgenic and gene-knockout mice have been applied to study the effects of ROS and their mechanisms. Various medium

suppress the ONOO– generation during the reperfusion [47]. 3.2 Down-regulation of nNOS

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N-methyl-D-aspartate (NMDA) receptor, trigger the activation of calcium channels, and then lead to NO production through stimulated nNOS

[39]

[Fig.3]. The excitotoxicity mediated by NO is caused by the over-activation of NMDA receptor. The

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uncontrolled entry of Ca2+ ions by the excessive activation of NMDA receptor produces a large amount of NO which contributes to the production of ONOO– and sets up a vicious cycle of cell death [Fig.3]. It is known that the mechanisms of

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the damage to ischemic brain cells are largely related to voltage-dependent calcium channels that induce Ca2 + Influx when

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they are open and the NMDA receptors as well as the voltage-dependent calcium channels are responsible for the Ca2 + Influx, which lead neurons to death [48]. Moreover, NO and its derivatives can modify proteins by means of the formation of

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nitrotyrosine adducts, which cause damage to DNA and induce the lipid oxidation in cellular membrane [49]. Treatment with nNOS inhibitor 7-nitroindozale (7-NI) markedly reduced neurological deficits, brain swelling, and infarct volume in rats subjected to MCAO. Enzymatic study and western blot analysis revealed that the activity of calpain and

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Cerebral ischemia and reperfusion can cause energy depletion, enhance the effect of glutamate through

caspase-3 in penumbra and ischemic core was significantly decreased in the rats treated with 7-NI compared with the control. Ming et al demonstrated that NO catalyzed by nNOS was involved in the ischemic neuronal injury through

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stroke [50]. Inhibiting NMDA receptor and calcium influx through an undirect pathway, Edv reduced nNOS activity possibly [Fig.3]. Hisano et al found that the suppressive effect of Edv on the glutamate neurotoxicity was achieved by inhibiting

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NMDA receptor in a nearly pure neuronal culture of fetal rat brain [51]. Intracellular free calcium concentration ([Ca2+]i) was significantly reduced by 100mM of Edv compared with the untreated control in I/R injured hippocampal cells via acute

nNOS activity and decrease NO synthesis [52]. Ajmal and Islam’s study showed

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which was beneficial to the suppression of

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glucose–oxygen deprivation and subsequent reoxygenation, the results of which reflected that Edv reduced Ca2+ overload

that caspase-3 activity was also significantly attenuated by the administration of Edv to rats with MCAO for 2 hrs followed

3.3 Down-regulation of iNOS

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by reperfusion for 22 hrs [34].

Mian et al confirmed that iNOS and nitrotyrosine were up-regulated in the infarction side of the brain subjected to MCAO [53]

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suppressing the activation of calpain and caspase-3-mediated apoptotic and/or necrotic cell death pathways in experimental

. They suggested that the up-regulation of tumor necrosis factor alpha (TNF-a) in ischemic stroke occurred partially

through iNOS incretion. Activated microglia could damage neurons by NO produced under the catalysis of iNOS, which

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mechanisms of neurodegenerative diseases. NO generated from iNOS is a source of the formation of ONOO– which causes further damage to neurons [Fig.3].

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Edv significantly suppressed NO production and reduced the activity of iNOS by inhibiting a non-NF-kB system in neuronal cultures oxidatively stressed by either ONOO– donor N-morpholinosydnonimine (SIN-1) or activated microglia. It

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could also significantly protect neuronal cells from death in a dose-dependent manner

[54]

. Edv treatment in vivo reduced

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microglial activation, iNOS expression, and nitrotyrosine formation in the mice with terminal cerebral ischemia followed by reperfusion [55]. Hiroshi et al has also demonstrated that Edv administration reduced iNOS expression in hippocampus after

4. Therapeutic perspectives

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transient ischemia in rats [47].

4.1 The combination of Edv with tissue plasminogen activator (tPA)

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inhibited neuronal respiration. As a result, it led to glutamate release and subsequent excitotoxicity in the inflammatory

Acute stroke, including AIS and acute hemorrhagic stroke (AHS), becomes a common medical problem and a major cause of death, which decreases the quality of life. Thrombolytic therapy is effective in ameliorating acute ischemia when

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therapy available [56], it is limited by a narrow therapeutic time window (3hrs) and some side effects, and also it causes a high risk of cerebral hemorrhage

[57]

. Non-specific free radical damages to cerebrovascular walls might be relevant to tPA’s

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side effects like intracerebral hemorrhage.

Hemorrhagic events are always related to the damage of BBB. Oxidative stress, matrix metalloproteinases (MMPs) and

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inflammatory mediators are involved in the change of BBB permeability in ischemic brain. Matrix metalloproteinase-9

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(MMP-9) has especially been associated with various complications including neuronal damage, apoptosis and BBB damage that leads to cerebral edema[58]. Watanabe et al observed that Edv suppressed the exacerbation of cortical edema and

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inhibit oxidative injury to BBB in rat focal I/R model[35]. Wang et al discovered that its treatment significantly reduced the inflammatory cytokines and BBB permeability and thus alleviated cerebral edema, compared to the control in rats with traumatic brain injury (TBI) [59]. The recent study conducted by Kenji and Hasegawa showed that Edv reduced MMP-9 level

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administrated early after ischemia attack. Although tissue plasminogen activator (t-PA) currently is the most effective

in serum and mitigated BBB disruption in conjunction in patients with AIS [60]. Moreover, the drug both in vivo and in vitro prevented from oxidative damage and protected the outer layer of BBB and tight junctions after the onset of cerebral

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Overwhelming evidences support that it is an imperative need to combine thrombolysis with antioxidant therapy. The co-administration of antioxidant drug with tPA may augment the value of the latter’s thrombolytic therapy and also reduce

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the risk of brain hemorrhage caused by tPA [62]. It was reported that Edv, UA and ebselen were all suitable candidates and provided synergistic neuroprotection in experimental thromboembolic models, for they endowed with potent antioxidant

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capacity and expressed fine pharmacokinetic property in blood when they were administered after acute stroke

[63,64]

. The

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combined therapy of thrombolytic plus Edv was first suggested by H. Yoshida et al as they found that hemorrhagic events induced by thrombolytic therapy might be reduced by Edv pretreatment and thus they considered that the therapy was [64]

. Edv mitigated the

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helpful to reduce the mortality of stroke and ameliorate neurological deficits in patients with stoke

adverse effects of tPA by protecting BBB, improving vascular reperfusion and decreasing oxidative stress, inflammatory cytokines and MMP activities when it synergized with acute tPA treatment in the model with a transient hypoxia-ischemia

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ischemia. The over expression of MMP was also suppressed by it [61].

(tHI)-induced thrombotic stroke

[65]

. In addition, it was reported that the administration of UA together with recombinant

tPA (rtPA) was beneficial for brain tissues to prevent them from damage induced by both acute stroke and thromboembolic

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response, prevented the degradation of UA in blood and extended the benefits of rtPA

[63,66]

. Moreover, ebselen, a

seleno-organic antioxidant which has GSH-Px–like property was found to have anti-inflammation when it was given to

EP

animals with embolic stroke. It could be beneficial if administered concomitantly with tPA for it significantly enhanced the neuroprotective activity of low-dose tPA [67].

C

The outcome of the combination of Edv and t-PA is tested in subjects with stroke in experiments. The results show that Edv [56]

AC

can extend the narrow therapeutic time window of tPA in rats

and more patients with the AIS can be rescued by the

combination of Edv and t-PA [68]. When tPA was infused 1h after embolization and Edv was given 3hrs after the ischemia in

ST

rabbits, the amount of microclots (mg) measured in brains with neurologic dysfunction was decreased by 50% that was significant compared to the control, which indicated that the combination might have substantially therapeutic benefits for the stroke and could also improve neurological behavior deficits

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stroke. This combined therapy reduced lipid peroxidation, ameliorated neurologic deficits, attenuated inflammatory

[69]

. Infarct volume was reduced with Edv when it was

injected twice into the rats with 90-min transient MCAO and followed by reperfusion produced by tPA treatment. The study demonstrated for the first time that exogenous tPA reduced the factors-Sema3A, Nogo-R, GAP43 and DCC, which were

24

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[68]

. Furthermore, Kono et

al reported that intravenous thrombolysis with rtPA combined with neuroprotective therapy with Edv had been applied to aged patients with ischemic stroke and they had a higher recanalization rate and a better modified Rankin Scale score 3 [70]

. It was indicated that Edv might be a proper candidate for

EP

months after stroke than the non-combination group

combination therapy with tPA to enhance the recanalization and reduce the hemorrhagic transformation in long-time

C

treatment.

AC

4.2. Extended application of Edv in chronic neurodegenerative disorders and I/R-related non-cerebral diseases Edv is a powerful free radical scavenger not only used in treatment for acute cerebral ischemic/reperfusion stroke, but also

ST

for a number of chronic neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis, as oxidative stress is widely believed to cause or aggravate the pathologies [71,72]. Yan et al and Li et al reported that Edv treatment significantly elevated cell viability, reduced apoptotic rate, attenuated oxidative stress, improved

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involved in promoting axonal growth and Edv ameliorated neural damages from acute ischemia

mitochondrial membrane potential and decreased the Bax/Bcl-2 ratio in neuroblastoma N2a cells in both PD and AD model [73,74]

. The treatment significantly improved intracerebroventricular cognitive damage induced by streptozotocin, which

25

[75]

TE D

markedly restored changes in oxidative stress

. Data from animal model and patients suggested that Edv was safe and

might delay the progression of functional motor disturbances via reducing oxidative stress and the deposition of SOD in

EP

amyotrophic lateral sclerosis (ALS) [76,77].

It was confirmed in previous study that Edv had protective effects against I/R-induced injury in many organs in addition to

[78]

and protected against I/R-induced oxidative damage to the mitochondria of rat liver [79]. It was reported

AC

leakage in liver

C

brain. For instance, the drug reduced hepatic I/R injury by suppressing oxidative stress, lipid peroxidation and enzyme

that Edv not only attenuated neurological dysfunction and oxidative DNA damage, but also ameliorated histopathological

ST

changes in rabbit spinal cords after I/R injury due to the obstruction of abdominal aorta[80]. As far as the cardioprotective effects of the drug were concerned, they were investigated in the modified cell-pelleting model of ischemi as well as in isolated adult rabbit ventricular cells subjected to exogenous oxidative stress. Results showed that the cardioprotection of

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evaluated in Morris water maze and step-down tests in rat model with sporadic Alzheimer's disease (sAD), meanwhile it

Edv raised the level of ascorbate and SOD and suppressed ROS production, and its potency was greater than that of other antioxidants [81]. Hori et al also found that the drug had protective effect on tourniquet-induced I/R injury of skeletal muscle

26

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[82]

.

Collectively, it is obvious that Edv, as a powerful free radical scavenger, is expected to be widely used in the treatment of

EP

oxidative stress-related diseases.

Conclusion

C

Edv is an excellent free radical scavenger that has been used in AIS both in clinical and experimental research and it exerts

AC

neuroprotective effect on ischemic brain. The potential mechanisms of Edv were expounded in the present review, for instance, it directly scavenged ROS such as •OH and RNS, up-regulated the activity of anti-oxidant enzymes, provided

ST

electrons to free radicals and affected receptors as well as intracellular ion concentration. The references concerning the various effects and mechanisms of the drug applied to cerebral ischemia mentioned in this review are listed in Table 1. Besides, the drug is potential in the treatment of other pathologies where acute ischemia reperfusion is linked to the

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in mouse hindlimb. MDA level was lowered and iNOS expression was decreased in the group of Edv treatment

pathogenesis of the disorder. And also, it has protective effect on chronic neurodegenerative disorders. It is concluded that the combination of free radical scavenger and tPA is feasible, and Edv enhances the recanalization and reduces the

27

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ST

AC

C

EP

application has broad prospects in clinical settings.

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hemorrhagic transformation caused by tPA. Generally speaking, Edv is safe and effective anti-oxidant, therefore its

28

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[1]Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010.

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Lancet 2013; 380(9859): 2095-2128.

[2]Eugene SF, Demopoulos HB, Seligman ML, Poser RG, Ransohoff J. Free radicals in cerebral ischemia. Stroke 1987;

C

9(5): 445-447.

AC

[3]Alexandrova ML, Bochev PG. Oxidative stress during the chronic phase after stroke. Free Radic Biol Med 2005; 39(3): 297-316.

ST

[4]Watanabe T, Yuki S, Egawa M, Nishi H. Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions. J Pharmacol Exp Ther. 1994; 268(3): 1597-1604. [5]Watanabe T, Egawa M. Effects of an antistroke agent MCI-186 on cerebral arachidonate cascade. J Pharmacol Exp

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amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler 2006; 7(4): 247-251.

42

Hidemi Yoshida et al Human [9]

Effects

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Model

Mechanisms

astrocytes/under Enhance the levels of NGF protein Enhance NGF expression via the JNK

hypoxia for 3 h

in astrocytes

pathway

C

(2010)

EP

Author

Delay the course of infarcts and Not mentioned

AC

Kazunori Toyoda et al Patients/ICAO [11]

edema, decrease mortality

(2004)

ST

Shimon Amemiya et al Rats/transient MCAO for Improve [12]

2h

(2005)

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Table 1 References concerning the effects and mechanisms of Edv

neurological

outcome, A decrease in Bax immunoreactivity

decrease total and cortical infarct and an increase in Bcl-2 expression volumes

through

a

Bax/Bcl-2

antiapoptotic mechanism

43

dependent

MCAO

TE D

[24]

mice/Permanent Ameliorate the tissue damage in Inhibit the increase of superoxide, the infarct rim, reduce infarct scavenge ROS in the neurons

(2004)

volumes

[27]

/treated with 1O2

EP

Yoko Nishinaka et al Neuronal B50 cells in rats Prevent from the impairment of React with 1O2 and change into another membrane

integrity

and

the compound

progression of cell death

Piyanart Sommani et al Human

Suppress 1O2 release with an IC50 Not mentioned

AC

C

(2010)

of approximate 0.3µM

neutrophils/stimulated

(2007)

with opsonized zymosan

Jiao L et al [22]

Wistar

(2011)

ischemia

ST

[28]

rats/cerebral Decrease delayed neuronal death Decrease MDA level, increase SOD

model

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Hideo Shichinohe et al Balb/c

intraluminal

by and

cognitive

vascular hippocampus

occlusion.

44

dysfunction

of level,

reduce

inflammatory

cytokines, suppress GFAP proliferation

Inhibit

(2006)

followed by reperfusion

JNK-c-Jun pathway with concomitant

for 45 min

inhibition of

EP

Ajmal Ahmad et al [34] Wistar rats/MCAO of 2h Reduce ischemic lesion volume, Reduce (2012)

followed by reperfusion improve neurological deficits

cerebral

and

the

MAPK activity radicals,

cholinergic

dysfunction, apoptotic damage

transient Protect the rat hippocampus from Prevent the increase in OH formation

ischemia

(10 ischemia-induced impairment

ST

min)

AC

(2005)

rats/

free

stress

C

for 22h Hiroshi Otani et al [47] Wistar

oxidative

TE D

SD rats/ BCAO model Reduce neuronal damage

and the expression of VEGF, neuronal and inducible NOS

Kenjiro Hisano et al Neurons from fetal rat Increase cell survival rate, protect Suppress ROS production [51]

brains/exposed to 50 uMneurons

(2009)

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Juan Wen et al [30]

glutamate for 10 min

against

neurotoxicity

45

glutamate

from Prevent from neuronal cell death Suppress the production of NO and

[54]

newborn

(2004)

mice/oxidative stressed by

C57/BL6 and neurotoxicity

or

activated

microglia

(2005)

ischemia

mice/60-min Reduce followed

reperfusion

[59] (2011)

by improve

volumes

and Reduce microglial activation, iNOS

neurological

deficit expression, and nitrotyrosine formation

Mitigate cerebral edema

Decrease hippocampal CA3 neuron

scores

ST

GuoHua Wang et al SD rats/TBI

infarct

C

C57/BL6

AC

Ning Zhang et al [55]

ROS

EP

SIN-1

TE D

neurona

loss and neuronal programmed cell death,

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Masahiro Banno et al Cortical

reduce

inflammatory permeability

46

oxidative

cytokines

and

stress, BBB

stroke

Decrease serum MMP-9 level, protect

TE D

(2012)

ischemic Reduce brain infarction

BCSFB and BBB

Violeta Lukic-Panin et Wistar rats/brain damaged Ameliorate oxidative damage

Protect outer layers of BBB (in vivo)

al [61]

and tight junctions (in vitro)

EP

by plasmin and tPA

C

(2010)

AC

Notes: Sprague-Dawley (SD); Mitogen activated protein kinase (MAPK); c-Jun NH2-terminal kinase (JNK); glial fibrillary

ST

acidic protein (GFAP); vascular endothelial growth factor (VEGF); blood cerebrospinal fluid barrier (BCSFB)

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Kenji Isahaya et al [60] Patients/acute

47

ST

JU EP

C

AC

TE D

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Fig.1 Chemical structure of Edaravone (Edv)

48

Fig.2 Mechanisms of Edv scavenging ROS Edv directly suppresses O2•− production through its increasing action on SOD activity as well

TE D

as its facilitating action on the process of highly reactive O2•− into H 2O2 and molecular oxygen, while the reaction that H 2O2 detoxified to form

nontoxic water is enhanced by antioxidaive enzymes including CAT or

EP

MPO-H2O2-chloride system. In the OH-scavenging pathway, Edv reacts

with both peroxyl and hydroxyl radicals via SET mechanism in which one electron is transferred to free radical turning into a stable oxidation

C

product 2-oxo-3-(phenylhydrazono)-butanoic acid(OPB). The bold

ST

AC

arrows in this figure express the regulated effects of the drug.

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GSH-Px etc. enhanced by the drug. It also suppresses 1O2 production in

49

Fig.3 Mechanisms of Edv scavenging RNS Three pathways of NO generation are showed in this figure. eNOS activity is increased by Edv,

TE D

while iNOS activity decreased in a direct way. In contrast, nNOS activity is probably reduced by the drug in an undirect pathway via Edv’s inhibition on NMDA receptor and calcium influx. The bold arrows in the

EP C AC ST JU

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figure show the regulated effects of the drug.

50

Edaravone's free radical scavenging mechanisms of neuroprotection against cerebral ischemia: review of the literature.

Free radicals and oxidative stress play key roles in cerebral ischemic pathogenesis and represent pharmacological targets for treatment. Edaravone (Ed...
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