CNS Drug Reviews

Vol. 12, No. 1, pp. 920

2006 The Authors
Journal compilation 2006 Blackwell Publishing Inc.

Neuroprotective Effects of Edaravone: a Novel Free

Radical Scavenger in Cerebrovascular Injury
Hiroshi Yoshida1, Hidekatsu Yanai1, Yoshihisa Namiki2,
Kayoko Fukatsu-Sasaki3, Nobuyuki Furutani1, Norio Tada1

1Division

of General Medicine, Department of Internal Medicine, Kashiwa Hospital,

Jikei University School of Medicine, Kashiwa, Chiba, Japan;
2Institute of Clinical Medicine and Research,
Jikei University School of Medicine. Kashiwa, Chiba, Japan;
3Toita Womens College, Shiba, Tokyo, Japan

Keywords: Brain ischemia Edaravone eNOS Neuroprotection Radical scavenger.

ABSTRACT
Recanalization and neuroprotection have been mainly targeted for the specific treatment of acute ischemic stroke. Free radicals play a crucial role in brain ischemic injury by
exacerbating membrane damage through peroxidation of unsaturated fatty acids of cell
membrane, leading to neuronal death and brain edema. Free radicals have been implicated
in stroke pathophysiology as pivotal contributors to cell injury. Edaravone (3-methyl-1phenyl-2-pyrazolin-5-one) is a novel potent free radical scavenger that has been clinically
used to reduce the neuronal damage following ischemic stroke. Edaravone exerts neuroprotective effects by inhibiting endothelial injury and by ameliorating neuronal damage in
brain ischemia. Edaravone provides the desirable features of NOS: it increases eNOS (beneficial NOS for rescuing ischemic stroke) and decreases nNOS and iNOS (detrimental
NOS). Post- reperfusion brain edema and hemorrhagic events induced by thrombolytic
therapy may be reduced by edaravone pretreatment. Increased productions of superoxide
and NO in the brain after reperfusion and a concomitant surge in oxygen free radicals with
increased NO during recirculation lead to formation of peroxynitrite, a superpotent radical. Edaravone, which inhibits oxidation and enhances NO production derived from increased eNOS expression, may improve and conserve cerebral blood flow without peroxynitrite generation during reperfusion. Clinical experience with edaravone suggests that this
drug has a wide therapeutic time window. The combination therapy (a thrombolytic plus
Address correspondence and reprint requests to: Hiroshi Yoshida, MD, PhD., Department of Internal Medicine, Kashiwa Hospital, Jikei University School of Medicine. 163-1 Kashiwashita, Kashiwa, Chiba 277-8567,
Japan; Tel.: +81 (4) 7164-1111 (ext. 3261); Fax: +81 (4) 7164-1126; E-mail: hyoshida@jikei.ac.jp

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H. YOSHIDA ET AL.

edaravone) is likely to target brain edema, reduce stroke death and improve the recovery
from neurological deficits in stoke patients.

BRAIN EDEMA AFTER ISCHEMIC INSULTS

AND FREE RADICALS
Recanalization and neuroprotection have been the main approaches in the specific
treatment of acute ischemic stroke. Thrombolytic treatment has been proven to be beneficial in the recanalization strategy targeted for rescue of nonfunctional but still viable
tissue (ischemic penumbra). However, brain edema, a consequence of ischemia/reperfusion-induced damage, needs to be addressed, since it is usually associated with highest
mortality after ischemic stroke.
During the last decades stroke research has been focusing on the mechanisms of cell
death that follows cessation of blood flow to the brain (16). Ischemic edema is a manifestation of severe ischemia that accompanies tissue injury. The occupation of space by brain
edema is the leading cause of cerebrovascular death within the first week after stroke (14).
Some molecular mechanisms and enzymatic degradation of vascular walls by several proteinases play a role in the pathophysiology of brain edema.
In ischemic stroke blood flow returns to the ischemic brain either spontaneously or as
an effect of a drug. The blood flow is usually redistributed from adjacent or collateral circulation. Although the restored blood flow counteracts ischemic injury and is essential for
the recovery of brain tissue, reperfusion of the damaged area can enhance brain edema.
Free radicals produced during reperfusion contribute to this detrimental paradoxic
response (24,27).
Brain edema is defined as an abnormal accumulation of fluid in the brain parenchyma,
leading to an enlarged brain volume. Depending on the site of fluid acquisition, brain
edema is classified into two main types. Cytotoxic edema, a swelling of cellular components, results from cellular metabolic disturbance. Vasogenic edema is caused by breakdown of the blood-brain barrier (BBB), thereby increasing its permeability to macromolecules and allowing fluid movement from intravascular site to extravascular space. The
consequences of cytotoxic and vasogenic edema are additive (16,27).
Cytotoxic edema depends on the duration and severity of the ischemic insult and is an
important indicator of ultimate infarct size. After cell injury, extravasated fluid in the
tissues increases brain volume and may lead to serious clinical consequences. Vasogenic
edema is usually formed later than cytotoxic edema and after cessation of cerebral blood
flow (CBF). It is the ultimate cause of brain volume increase after ischemic stroke that
leads to clinical deterioration. This deleterious edema formation is associated with the oxidative stress due to formation of free radicals during ischemia/reperfusion.
A new agent with an antioxidant property can be expected to alleviate the consequences of brain ischemia. Edaravone has been discovered in a program that focused on
free radical-scavenging activity of phenol compounds (9,32). Many compounds containing keto-enol tautomerism have been investigated and edaravone was selected as one
of the more effective compounds. The evidence for its effectiveness was derived from in
vitro and in vivo studies described below.

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FREE RADICAL ASSAULT IN ISCHEMIC STROKE

AND EFFECTS OF EDARAVONE
From 1984, the antioxidant property of phenolic compounds with keto-enol tautomerism, including 2-pyrazolin-5-ones, were tested in vitro for their free radical scavenging
activity and inhibition of lipid peroxidation, and in vivo for protection in animal models
against brain damage caused by ischemia/reperfusion. As described in the following sections edaravone was found to protect from vascular endothelial cell injury in vitro and to
prevent formation of brain edema, neurological deficits and delayed neuronal cell death in
vivo. A recent Japanese multicenter randomized clinical trial has demonstrated that edaravone, administered within 72 h after onset of the ischemic stroke, significantly reduces
brain infarct volume and produces sustained benefits in functional outcome during 12
months follow-up period (37). Edaravone was infused at a dose of 30 mg, twice a day for
14 days, to acute ischemic stroke patients. The functional outcome was evaluated using
the modified Rankin Scale at 3 months after onset of stroke or at a discharge within 3
months. A significant improvement in functional outcome was found in the edaravone
group as compared with placebo, indicating the potential usefulness of edaravone as a
neuroprotective agent. Edaravone has been approved in Japan since 2001 as a neuroprotective agent, scavenging free radicals, for the treatment of acute cerebral infarcts within
24 h after onset.
Free radicals have been implicated in stroke pathophysiology as pivotal contributors to
brain cell injury (16,15,22,34). After brain damage, caused by either ischemic or hemorrhagic stroke, physiological systems involved in the removal of the excess of free radicals
are impaired and the formation of free radicals is increased. The increased amount of free
radicals damages all cellular components, including DNA, lipids, and proteins, leading to
injuries of neurons, glial cells, nerve fibers, and blood vessels.
Since Flamm et al. reported the pathological relevance of free radicals in the components of cell membrane to cerebral ischemia, many investigators demonstrated therapeutic
effectiveness of free radical scavenging in the experimental ischemic stroke (8,16). Oxidative stress damages blood-brain barrier (BBB), leading to vasogenic brain edema. Chan
et al. demonstrated that superoxide radicals generated by xanthine/xanthine oxidase system cause vasogenic brain edema (4). The oxidation of hypoxanthine and xanthine to uric
acid by xanthine oxidase is coupled to the reduction of oxygen to superoxide. Hydrogen
peroxide generated by xanthine oxidase, in addition to superoxide radicals, contributes to
brain edema after stroke. However, the direct effects of free radicals are limited temporally and spatially because most radicals are generated intracellularly and have short halflives. Thereby, most free radicals are locally concentrated, but superoxides and hydrogen
peroxide readily cross the cell membrane and have extracellular remote effects. For example, free radicals generated after cerebral ischemia contribute to the neuronal injury and
the brain edema aggravation mainly by activating lipoxygenase pathway in the arachidonate cascade, and, therefore, scavenging free radicals and prevention of lipid peroxidation
can directly suppress brain edema (3,4,21,25,41).
Living systems constantly encounter free radicals, which are generated by enzymatic or
non-enzymatic mechanisms, leading to oxidative stress. Polyunsaturated fatty acids of cellular membrane phospholipids are particularly vulnerable to free radical assault and undergo lipid peroxidation, resulting in the loss of structural and functional integrity of cells.

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H. YOSHIDA ET AL.

Membrane lipid peroxidation has been implicated

in numerous pathological conditions such as cancer, diabetes, atherosclerosis, ischemia-reperfusion
N
injury, and various vascular pathology, including
ischemic stroke and its consequences (3,7,15,21).
N
Reactive oxygen species (ROS) and lipid peroxides-mediated endothelial barrier dysfunction
H3C
has been implicated in the pathogenesis of cerebroFig. 1. Chemical structure of edaravone.
vascular disorders.
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5one), a novel radical scavenger (Fig. 1) protects
neurons by inhibiting endothelial injury and by
ameliorating neuronal damage caused by brain ischemia. Edaravone was found to have
promising antioxidant effects: it quenches hydroxyl radical (OH) and inhibits OH-dependent and OH-independent lipid peroxidation (41,44). Edaravone exerts inhibitory effects on both water-soluble and lipid-soluble peroxyl radical-induced peroxidation systems. Its effects are, therefore, similar to the combined effects of vitamins C and E (43).
Edaravone inhibits both nonenzymatic lipid peroxidation and lipoxygenase pathway and
has potent antioxidant effects against ischemia/reperfusion-induced vascular endothelial
cell injury, delayed neuronal death, brain edema, and concomitant neurological deficits
(41).
As described above, edaravone was selected from the phenolic compounds containing
keto-enol tautomerism. These compounds were tested because phenol compounds are
known to exert great radical-scavenging activity. Two activities were considered in the selection of edaravone: quenching of hydroxyl radicals and prevention of autoxidation of rat
brain homogenates. As elaborated below, substantial evidence indicates that edaravone inhibits and/or prevents brain edema after ischemia, tissue injury, delayed neuronal death,
vascular endothelial cell injury, and neurological deficits (1,20,29,41,44).

BIOCHEMICAL MECHANISMS
OF ACTION OF EDARAVONE
Edaravone can exert a wide range of inhibitory effects on water-soluble and lipidsoluble peroxyl radical-induced peroxidation systems, and appears to display combined
properties of both, vitamin C and E (41,43,44). Yamamoto et al. (43) reported the antioxidant effect of edaravone in the experimental oxidation system with phosphatidylcholine
(PC) unilamellar liposomes. The oxidation of soybean PC liposomes was performed under
aerobic conditions at 37C in the absence or presence of edaravone, vitamin E, or vitamin
C. The oxidation was initiated with either a water-soluble initiator (AAPH) or a lipidsoluble initiator (AMVN). In the PC liposome oxidation system with AAPH, vitamin C is
one of the best antioxidants because free radicals are produced in the aqueous phase.
Edaravone can inhibit the PC liposome oxidation as efficiently as vitamin C, suggesting
that edaravone is capable of scavenging free radicals in the aqueous phase. In the PC
liposome oxidation system with AMVN, vitamin E is one of the best antioxidants because
in this system the oxidation-initiating radicals are present in the lipid phase. Edaravone

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EDARAVONE
O

13
O

LOO

LOO

N
H3C

H3C

Edaravone anion

Edaravone radical
O

OO

N
N

H3C

O
O

H2O

COOH
HN

N
H3C

N
H3C

4,5-dione

OPB

Fig. 2. Proposed interaction of edaravone with free radicals. Electron donation from edaravone to free radicals
produces peroxyl anion and edaravone radical, which is transformed to 4,5-dione. OPB is generated by hydrolysis reaction of the 4,5-dione. LOO, lipid peroxyl radical; LOO, lipid peroxyl anion; 4,5-dione, 3-methyl-1phenyl-2-pyrazolin-4,5-dione; OPB, 2-oxo- 3-(phenylhydrazono)-butanoic acid.

can inhibit the PC liposome oxidation as efficiently as vitamin E and can spare vitamin E,
suggesting that it is capable of scavenging free radicals in the lipid phase and presumably
reducing vitamin E radicals.
Edaravone can scavenge not only hydroxyl radicals but also other free radicals, although it has no major effect on superoxide anion radicals. Edaravone apparently traps
hydroxyl radicals and inhibits OH-dependent lipid peroxidation or tyrosine nitration induced by peroxynitrite (ONOO). Lipid peroxidation starts with lipid radical (L) production after free radical-mediated extraction of proton from unsaturated fatty acid. Subsequently lipid peroxyl radical (LOO) is generated by addition of oxygen atom, and a
further L is produced by LOO-mediated extraction of proton from another unsaturated
fatty acid. Edaravone can inhibit lipid peroxidation by scavenging not only hydroxyl radicals but also other free radicals including LOO. Under physiological conditions, 50% of
edaravone is present as an anion form, and electrons released from edaravone anion exert
radical scavenging. Subsequently, edaravone radicals are generated. They react readily
with oxygen atoms, and form peroxyl radical of edaravone, and eventually 2-oxo-3-(phenylhydrazone)-butanoic acid (OPB) (Fig. 2) (43).

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H. YOSHIDA ET AL.

ROLE OF NITRIC OXIDE (NO)

IN THE PHARMACOLOGY OF EDARAVONE
Edaravone has been reported to protect cells against cytotoxicity of hydroperoxyeicosatetraenoic acids (HPETEs), arachidonate oxidation products generated by lipoxygenase
and potent toxins for vascular endothelial cells (40). HPETE, 30 M, severely damaged
bovine aortic endothelial cells after 2 h of incubation, while edaravone, 1 M, -prevented
HPETE-induced cell damage. Oxidized low-density lipoproteins (LDL) are known to play
a critical role in atherogenesis and vascular dysfunction. They are generated by endothelial cells, smooth muscle cells, and macrophages in vascular wall (35,36,42). Edaravone, at 6 to 24 M, inhibits endothelial cell-mediated LDL formation (45).
Post-ischemic reperfusion induces tissue damage in virtually all organs. This damage is
likely to be produced by the accelerated formation of several reactive oxygen species including superoxide, hydroxyl, and nitric oxide (NO) radicals. NO is generated by inducible NO synthase (iNOS, type II NOS). iNOS, expressed in macrophages, neutrophils,
and microglia following immunological inflammatory stimuli, may also contribute to the
late stage tissue injury (24,30). By contrast, endothelial NOS (eNOS, type III NOS) may
play a protective role, helping to preserve blood flow (24,30). eNOS-derived NO is
thought to promote collateral circulation and microvascular flow, whereas neuronal NOS
(nNOS, type I NOS; a Ca2+ calmodulin-dependent enzyme)- or iNOS-derived NO are detrimental to ischemic brain. Cerebral function damage after transient global ischemia has
been reported to be in part due to nitrosative stress via upregulated iNOS. Post-ischemic
NO production is reduced by iNOS inhibitor and this effect leads to restoration of longterm potentiation in the post-ischemic hippocampus (5,18,19,30,33). Excessive NO production by nNOS is cytotoxic and, nNOS knockout animals are resistant to ischemia
(5,19). Conversely, eNOS knockout animals develop larger infarcts because NO derived
from endothelial origin promotes survival by ameliorating residual blood flow during
ischemia (18,33). However, the role of eNOS may be complicated because endothelial NO
surge during reperfusion may contribute to brain injury by causing formation of peroxynitrite, a powerful oxidant, and in turn, may ameliorate microvascular circulation by inhibiting aggregations of platelets and neutrophils (10,11). A recent report has demonstrated that transient ischemia increased expression of all the three NOS isoforms at
protein levels when evaluated 4 days after ischemic insult in rat brain, and that edaravone
treatment on Day 0 (immediately after reperfusion) downregulated expressions of nNOS
and iNOS, but upregulated eNOS expression in rats (30). These favorable NOS features
may explain the alleviating effect of edaravone on ischemia-induced impairment. At
10 M (concentration similar to that achieved in serum in clinical use), edaravone increased mRNA and protein expression of eNOS in human umbilical vein endothelial cells
(HUVECs). This effect was presumably due to increased stability of eNOS mRNA. This
finding suggested that edaravone may reverse impaired eNOS expression induced by oxidized LDL, and consequently endothelial dysfunction and atherosclerosis as shown in
Fig. 3 (45). Quantitative analysis of Western blot data revealed that edaravone increases
eNOS expression to the levels twice as high as in controls, and that it reverses oxidized
LDL-mediated reduction in eNOS expression. In addition, Zhang et al. studied the effects
of NOS inhibition on cerebral ischemic damage in spontaneously hypertensive rats with
permanent middle cerebral artery occlusion (MCAO) (47). They found that NOS inhi-

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EDARAVONE

15

eNOS

Lane 1: control
Lane 2: edaravone
Lane 3: oxidized LDL
Lane 4: edaravone and oxidized LDL
GAPDH

Fig. 3. Edaravone enhances protein expression of eNOS and reverses oxidized low-density lipoprotein
(LDL)-mediated reduction in eNOS in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated for 20 h with 12 M edaravone and/or 40 g/mL of oxidized LDL. Protein expression of eNOS was evaluated by Western analysis followed by internal control glyceraldehydes 3-phosphate dehydrogenase (GAPDH).

bition worsens ischemic damage when instituted shortly after onset of ischemia and does
not affect or reduce brain damage when administered later. Taken together, vascular effects of NO are likely to be beneficial in the early stages of permanent focal cerebral
ischemia, supporting the use of edaravone in the therapy of acute ischemic stroke in its
initial stage.
In the clinical practice thrombolytic therapy is administered to most stroke patients
upon the arrival at the hospital, usually within several hours after stroke onset. At a later
stage antithrombotics and recirculation carry more risk of brain hemorrhage and edema
(13). Increased production of superoxide and NO in the brain is found after reperfusion,
and a concomitant surge in oxygen free radicals with increased NO formation during recirculation leads to formation of peroxynitrite (12,16). The overproduction of these radicals may play a pivotal role in reperfusion-induced brain injury. In this regard, edaravone,
which inhibits oxidation and enhances NO production derived from increased eNOS expression, may improve or conserve vascular blood flow without increasing peroxynitrite
formation during reperfusion (45). It has been recently reported that in mice with MCAO,
edaravone, administered within 6 hours after onset of reperfusion, reduces infarct volume
and improves neurological deficits. During the early stage of ischemic insult edaravone
suppresses accumulation of 4-hydroxy-2-nonenal (HNE)-modified protein and 8-hydroxy-deoxyguanosine (8-OHdG) in the penumbra area, while during later stages it reduces
microglial activation, iNOS expression, and peroxynitrite formation in astrocytes (46).

FUTURE THERAPEUTIC PERSPECTIVES

The mechanisms of brain injury related to ischemia/reperfusion and the neuroprotective mechanisms of action of edaravone, based on the in vitro and in vivo evidence described above, are schematically shown in Fig. 4. Edaravone inhibits lipid peroxide accumulation by scavenging free radicals generated during brain ischemia/reperfusion, and
thereby attenuates vascular and neuronal cell injury. In addition, edaravone improves ce-

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Free arachidonate

H. YOSHIDA ET AL.
Fig. 4. Development of brain injury during ischemia/reperfusion, and proposed mechanisms of the neuroprotective action of edaravone. ATP, adenosine triphosphate; AMP,
adenosine monophosphate; HPETE, hydroperoxyeicosatetraenoic acid; HETE, hydroxyeicosatetraenoic acid; PGG2, prostaglandin G2; PGH2, prostaglandin H2; L, alkyl; , site
of the inhibitory effect of edaravone.

EDARAVONE

17

rebral blood flow by increasing eNOS and, because of its antioxidant property, without increased production of peroxynitrite. It can be concluded that edaravone may attenuate vascular endothelial and neuronal injuries by inhibiting oxidative stress and by enhancing
eNOS activity.
One major limitation of stroke therapy is the lag time from onset of stroke to the beginning of treatment because many cell death mechanisms start within minutes. Although
peri-ischemic areas (penumbra) may be salvaged by recanalization, this treatment should
be launched within 36 h after onset of stroke. Therefore, the number of patients eligible
for thrombolytic therapy is, to begin with, limited. However, unlike with recanalization,
there is a wide therapeutic time window for brain edema because the fluid accumulation in
the brain progresses for days after onset of stroke. As reported recently, edaravone has excellent neuroprotective effects in the cortical area (but not in the subcortical area) regardless of cerebral blood flow (2). Cerebral cortex contains the major part of ischemic penumbra, in which cells are still only mildly damaged and may undergo apoptosis rather
than necrosis (26). Therefore, cerebral cortex could be salvageable after ischemic events
(17,28). In experimental models of focal brain ischemia infused with edaravone for
90 min its major oxidation product (2-oxo-3-(phenylbutazono)-butanoic acid, OPB) was
found in the penumbra area. This finding indicated that edaravone is likely to protect brain
by reacting with oxygen radicals formed in the penumbra (20).
Although numerous studies have shown that antioxidants or radical scavengers could
reduce infarct volume and brain edema in animal experiments, clinical trials of neuroprotective drugs were often disappointing (16). In this regard, the report from The Edaravone
Acute Brain Infarction Study Group (37) demonstrated clinical efficacy of edaravone and
importance of animal studies described above. Further 2 reports of intriguing clinical
studies with edaravone have come. Toyoda et al (38) reported that the early treatment with
edaravone was associated with delayed evolution of infarct volume and brain edema and
decreased mortality during the acute stage in stroke patients with internal carotid artery
(ICA) occlusion. These beneficial effects of edaravone, conceivably due to anti-edematous action as well as antioxidant action related to protection of microvascular barrier
against ischemic injury, also contributed to hemorrhagic transformation because a large
infarct with mass effect due to infarct volume and brain edema augments hemorrhagic
transformation during clinical course. Although edaravone markedly improved the acute
survival rate for stroke patients with ICA occlusion, it did not improve chronic functional
outcome among the survivors. This failure seems to have causal relation with insufficient
prevention of evolution of infracts and edema on days 57 after onset in contrast to antistroke effect favorably found on days 2. However, this study is a small-sized study and not
a double-blind, placebo-controlled, randomized trial unlike The Edaravone Acute Brain
Infarction study, and therefore there are some limitations for interpretation of the results.
Tsujita et al (39) reported effects of edaravone on reperfusion injury in patients with acute
myocardial infarction (AMI). This study was a randomized, placebo-controlled, openlabel study in patients with initial AMI admitted within 6 h of symptom onset. Edaravone
(30 mg) was intravenously infused for 10 min just before reperfusion, and saline was administered as placebo. Edaravone reduced increase in creatine kinase, increased left ventricle ejection fraction just after reperfusion, and decreased reperfusion arrhythmia as
compared with placebo. Therefore, edaravone administration before reperfusion treatment
of AMI may be associated with smaller myocardial infarcts and better clinical outcome

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H. YOSHIDA ET AL.

and these beneficial effects provide further evidence to support the concept that free radicals play a pivotal role in reperfusion injury in AMI.
Free radicals play a crucial role in brain ischemic injury by exacerbating membrane
damage through the peroxidation of unsaturated fatty acids of cell membrane, leading to
neuronal death and brain edema. Edaravone is a potent free radical scavenger that has
been used clinically to reduce neuronal damage following ischemic stroke. However, the
most severe form of brain edema in ischemic stroke is observed when both, free radicalmediated cell injury and protease-mediated matrix degradation, act in combination. Therefore, the beneficial effect of edaravone on ischemic stroke may be enhanced in combinations with other treatments. For example, a recent report has showed that combination
therapy (edaravone plus tissue plasminogen activator) significantly increases the survival
rate of rats with transient MCAO and reduces the infract volume and hemorrhage, and that
the neuroprotective effect of edaravone treatment is dependent on reduced accumulation
of lipid peroxidation products (48). Post- reperfusion brain edema and hemorrhagic events
induced by thrombolytic therapy may be reduced by free radical scavenging.
Finally, a recent publication described the effects of edaravone on endoplasmic reticulum (ER) stress (31). ER stress, a cellular stress pathway induced by the accumulation of
unfolded proteins in the ER, is involved in cellular death mechanisms. Although cerebral
ischemia is a pathophysiological ER stressor (23), edaravone can protect against ER dysfunction induced by cerebral ischemia. The restoration of ER stress in addition to the radical scavenging action may be a novel neuroprotective mechanism because peroxynitrite is
an ER stress inducer (6), and the expansion into further applications of edaravone shall be
performed by further clinical and basic research evidences.

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