Expert Opinion on Investigational Drugs

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Advanced neuroprotection for brain ischemia: an

alternative approach to minimize stroke damage

Maria Irene Ayuso & Joan Montaner

To cite this article: Maria Irene Ayuso & Joan Montaner (2015) Advanced neuroprotection for brain
ischemia: an alternative approach to minimize stroke damage, Expert Opinion on Investigational
Drugs, 24:9, 1137-1142, DOI: 10.1517/13543784.2015.1065040

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 Editorial

Advanced neuroprotection for

brain ischemia: an alternative
approach to minimize stroke
1. Introduction
2. Expert opinion
damage
Maria Irene Ayuso* & Joan Montaner†
Neurovascular Research Group, Institute of Biomedicine of Seville, Hospital Universitario Virgen del
Rocio, Seville, Spain

Despite decades of research on neuroprotectants in the fight against ischemic

stroke, no successful results have been obtained and new alternative
approaches are urgently needed. Translation of effective candidate drugs in
experimental studies to patients has systematically failed. However, some of
those treatments or neuroprotectant diets which demonstrated only benefi-
cial effects if given before (but not after) ischemia induction and discarded
for conventional neuroprotection, could be rescued in order to apply an
‘advanced neuroprotection strategy’ (ADNES). Herein, the authors discuss
how re-profiling those neuroprotective candidate drugs and diets with the
best potential, some of which are mentioned in this article as an ADNES,
may be a good approach for developing successful treatments that protect
the brain against ischemic damage. This novel approach would try to protect
the brain of patients who are at high risk of suffering a stroke, before damage
occurs, in order to minimize brain injury by having the neuroprotectant drug
or diet ‘on board’ if unfortunately stroke occurs.

Keywords: advanced neuroprotection, brain ischemia, diet, ischemic stroke, neuroprotection,

nutrition intervention, w-3, pharmacological intervention, prevention, statin

Expert Opin. Investig. Drugs (2015) 24(9):1137-1142

1. Introduction

Stroke is one of the leading causes of death in developed countries and the main
cause of permanent disability in adults. One in six people will suffer a stroke during
their life. Thus, it is a true vascular epidemic and a medical emergency that must be
effectively addressed. Therefore, all measures aimed at identifying new therapeutic
strategies and implementation of prevention is crucial [1].
After several decades of research on neuroprotectants against ischemic stroke,
only unsuccessful results have been obtained and no single neuroprotectant agent
has been approved. Therefore, new alternative approaches are necessary to win
this battle. Translation from candidate drugs effective in experimental studies to
patients has systematically failed, however, some of those treatments which demon-
strated only beneficial effects if given before (but not after) ischemia induction,
discarded therefore for conventional neuroprotection, could be rescued in order to
apply an ‘advanced neuroprotection strategy’ (ADNES). In this review, we will
try to support and elaborate more on this alternative strategy and on the candidate
treatments with the best profile to be used for ADNES.
Ischemic stroke is mainly due to a blockage in cerebral arteries decreasing blood
flow and leading to brain infarcts. This process causes a severe metabolic stress and
triggers several cellular mechanisms known as ischemic cascade, which includes
excitotoxicity, calcium influx, oxidative stress, a secondary microcirculation damage,

10.1517/13543784.2015.1065040 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 1137
All rights reserved: reproduction in whole or in part not permitted
M. I. Ayuso & J. Montaner
Table 1. Potential groups of patients that might be
target of ADNES and that would require short- or
long-term ADNES.
Groups of patients with high risk of brain ischemia (candidates
for short-term ADNES)
Patients with intracranial stenosis or carotid disease that receive
angioplasty and stenting
Patients undergoing carotid endarterectomies
Patients receiving endovascular or surgical treatment for cerebral
aneurysms
Cardiac patients receiving heart surgery
Groups of patients with high risk of stroke (candidates for
long-term ADNES)
Patients with accumulation of several vascular risk factors such
as hypertension, diabetes and dyslipidemia
Old patients with unhealthy diets, physical inactivity and obesity
Patients with silent brain infarcts
Patients with intracranial and carotid stenosis
Transient ischemic attacks
Patients with arrhythmias (such as atrial fibrillation)
ADNES: Advanced neuroprotection strategy.
inflammation and apoptosis. This is a dynamic process that
produces an irreversible loss of cell viability and finally drives
to neuronal death [2].
To date, intravenous thrombolysis with tissue plasminogen
activator is the only drug approved and available for the acute
phase of ischemic stroke. The aim of this treatment is to
restore blood flow, preventing the progress of the ischemic
cascade and limiting the damage caused by ischemia. In recent
months, a real revolution on reperfusion strategies using
thrombectomy devices (stent retrievers) adds hope to improve
efficacy and extend time-windows of conventional reperfusion
therapies [3].
Therefore, it seems clear that ‘plumbers’ are beating
‘chemists’ in the field of stroke; nevertheless, strict inclusion
criteria for reperfusion eligibility (including a therapeutic win-
dow limited to 4.5 h after symptoms onset) restricts thrombo-
lytic opportunity to < 5% of stroke patients [4]. Thus,
investigating new ways of implementing neuroprotective
strategies is essential to limit brain damage in most of the
stroke patients who remain untreated.
Two major strategies can be afforded in stroke prevention,
one related to health policies (e.g., reducing salt content in
foods) and another more medical strategy consisting of iden-
tifying target populations at highest vascular risk to actively
prevent the occurrence of stroke. It is well known that there
are several groups of patients with high risk of brain ischemia
such as patients undergoing carotid or heart surgery or
patients with huge risk of having a stroke in the coming
days or weeks, such as patients with silent brain infarcts, intra-
cranial stenosis, transient ischemic attacks and heart arrhyth-
mias (Table 1).
Our hypothesis is that in some of these groups the risk is so
high that it would make sense to start neuroprotective treat-
ments before an ischemic event occurs. Our goal would be
1138 Expert Opin. Investig. Drugs (2015) 24(9)
to protect the brain at risk before the stroke takes place and
to minimize brain damage when it occurs.
The aim of ‘classical’ neuroprotection is to prevent death of
vulnerable cells in the ischemic penumbra which surrounds
the infarct core. This tries to interfere in the early stages of
the ischemic cascade with the purpose of limiting the exten-
sion of brain injury.
However, those classical approaches have systematically
failed [5]. In fact, more than a thousand compounds have
been tested and hundreds of clinical trials performed. Many
of those neuroprotective agents have shown beneficial effects
in animal models of cerebral ischemia, but none has proven
to reduce tissue damage and improve the neurological out-
come in human stroke patients when given at patient’s arrival
to emergency departments. Translation from animal studies
to human patients has failed due to several caveats both at
the lab and at the clinic and mainly driven by differences
between animal models and human studies and the time
window between ischemia and treatment. Stroke therapy
academic industry roundtable recommendations try to solve
part of those discrepancies proposing that after initial evalua-
tions in young, healthy male animals, further studies should
be performed in females, aged animals and animals with
comorbid conditions such as hypertension, diabetes and
hypercholesterolemia [6]. Moreover, in many of the preclinical
studies, the animals are pre-treated with the neuroprotective
agent, and in fact several of these neuroprotective agents,
administered before the induction of the experimental ische-
mia yielded good results, but were discarded due to absence
of effectiveness when administered minutes or hours after
occlusion of a cerebral artery as recommended by the stroke
therapy academic industry roundtable criteria.
After systematic failures in the translation process, the sci-
entific community is trying to address these methodological
issues to find effective neuroprotectant for acute stroke and
as for example in the MULTI-PART initiative multicenter
experimental studies mimicking human clinical trials are
planned [7].
However, we believe that not all those previous results
should be abandoned forever and that there is still potential
for the use of those neuroprotective agents in other scenarios
that are not the urgent treatment of stroke at the emergency
department.
The acquired knowledge from past failed studies might be
useful if re-profiled into new therapeutic opportunities such
as ADNES to protect the brain at risk in order to minimize
part of the brain injury that will occur (Figure 1).
Are there any data supporting this new strategy? Yes, in fact
there are studies showing that the use of statins, hypothermia
or PSD-95 inhibitors has shown promise as neuroprotectants
for stroke, specifically when used in an advanced manner.
For example, patients using statins before a stroke had a
better neurologic outcome [8] and are therefore beginning to
be tested in acute stroke [9].
 Advanced neuroprotection for brain ischemia: an alternative approach to minimize stroke damage

Preventive Neuroprotectant
diets drugs

Reprofile for
ADNES

Original intended use: Original intended use:

To avoid appearance To treat stroke after it
of stroke Stroke occurs

High-risk
Long-term ADNES Without ADNES Short-term ADNES
candidates candidates

With ADNES

Figure 1. Neuroprotectant drugs or preventive diets which demonstrated beneficial effects if given before ischemia
induction and discarded for conventional neuroprotection could be rescued in order to apply ‘advanced neuroprotection
strategy’ (ADNES). ADNES is a novel approach that would try to protect the brain at risk before stroke occurs, to prevent and
especially to minimize brain injury in order to be applied to patients at high risk for stroke. Images show the possible
differences in brain damage after stroke in a patient at high risk of cerebral ischemia with or without ADNES.
ADNES: Advanced neuroprotection strategy.

Hypothermia is currently used in patients to prevent sec-
ondary brain ischemia after cardiac arrest and resuscitation [10]
and is being tested in acute stroke in clinical trials such as
EUROHYP [11].
Also the neuroprotective compound NA-1, an inhibitor of
PSD-95, has been tested in patients with iatrogenic stroke
occurring during aneurysm repair (ENACT trial) anticipating
ischemia limited its consequences [12].
These results will probably encourage additional trials in
carotid surgery, open heart surgery and many other invasive
treatments with a risk of brain injury with such type of strat-
egies (stroke, hypothermia, NA-1) to be given for a short
period of time before the intervention (what we named
short-term ADNES).
In addition, the use of several compounds with an excellent
safety profile which demonstrated its neuroprotective effect in
different models of cerebral ischemia models would allow
them to be administered for long periods of time before the
stroke. The paradigm of a safe compound to be given for
months or years would be a neuroprotective diet.
Some diets used also for prevention of cardiovascular events
such as w 3-enriched diets have shown to reduce infarct size
(fish oil-enriched food for 6 weeks) as an example of
ADNES [13].
The target population of that strategy would be people with
accumulation of vascular risk factors, with high risk of suffer-
ing a stroke. Stroke might occur weeks, months or years after
initiation of ADNES that would be what we have named a
long-term ADNES.
In fact, the type of diet of our elders can contribute to neu-
rovascular disease. Recently, this effect has been demonstrated
in a clinical trial with the Mediterranean diet that supple-
mented with extra-virgin olive oil or nuts reduced the risk of
myocardial infarction, stroke or cardiovascular death by
30% [14]. In addition, we hypothesize that the course of ische-
mic injury, if it occurs, would be different depending on the
patient diet. The diet would not only act as a preventive strat-
egy counteracting vascular risk factors, but it also would be a
factor that could modulate the degree of injury when a cere-
bral artery occlusion occurs.
It is well known that diets rich in fiber, low fat and low sugar
content are possibly positively associated with lower cardiovas-
cular risk and that nutritional qualities of each diet are deter-
mined by their components. For example, seafood intake is
inversely related to the cardiovascular and cerebrovascular
mortality [15]. Moderate consumption of tuna or other fish,
except fried fish, was associated with lower incidence of sub-
clinical brain infarcts and white matter abnormalities on MRI
examinations [16]. The intake of fish with high content in w-3
fatty acids may have clinically important benefits to health.
In Table 2, we show that some of those compounds dis-
carded for conventional neuroprotection could be rescued in
order to be applied in advanced neuroprotection and also
some natural products and natural product-derived com-
pounds known for having neuroprotective effects.
Among those bioactive compounds are the flavonoids. It is
well known that flavonoids from fruits and vegetables have a
positive impact on blood pressure, vascular function and

Expert Opin. Investig. Drugs (2015) 24(9) 1139

M. I. Ayuso & J. Montaner

Table 2. Potential treatments to apply the advanced neuroprotection strategy.

Neuroprotective agent Bioactive compounds Properties

Candidates for short-term ADNES

Glutamate blockers Tat-NR2B9c (NA-1) Anti-excitotoxicity, inhibitor of post-synaptic density-95 protein/nNOS
complex
Magnesium sulfate Anti-excitotoxicity, NMDA ion channel blocker; physiological
calcium channel blocker, neuroprotection
Scavenger of ROS NXY-059 Antioxidant, free-radical-trapping, neuroprotective
Cytokine antagonists IL-1ra Inhibitor at the IL-1 receptor. Anti-inflammatory
Statins Simvastatin HMG-CoA reductase inhibitors; pleiotropic activities
Antibiotics Minocycline Anti-inflammatory, antioxidant, anti-apoptotic, inhibitor of microglia
Immunosuppressant FK506 (tacrolimus) Anti-inflammatory, anti-apoptosis, inhibitor of calcineurin activity
Hormone Melatonin Antioxidant, free radical scavenging, neuroprotective, anti-inflammatory
Hematopoietic growth Erythropoietin Anti-apoptosis, neuroprotective
factor
Candidates for long-term ADNES
Fish and vegetables oil Polyunsaturated fatty acids Reduces cardiovascular risk, decreases blood pressure and blood
(w-3) triglyceride concentrations, decreases inflammation, improve vascular
function, neuroprotective
Grapes, red wine Resveratrol Antioxidant, upregulates antioxidant enzymes, prevents lipid peroxidation,
anti-inflammatory, anti-cancerous, reduces cardiovascular risk
Olive oil Monounsaturated fatty acids, Decreases LDL levels, increases HDL levels, antioxidant, decreases oxidation
vitamin E, polyphenols of LDL, decreases proinflammatory and prothrombotic mediators,
anticancerous, neuroprotective
Onion Quercetin Antioxidant, free radical scavenger, anti-inflammatory, neuroprotective,
inhibition of MMP activity, BBB protection, reduces excitotoxicity,
anti-aggregant, anti-hypertensive, anti-atherosclerotic
Tomato Carotenoids, lycopene Antioxidant, anti-inflammatory, antitumor activity, reduces cardiovascular
risk, hypocholesterolemic, reduces blood pressure, neuroprotective
Green tea Teanin, catechins Reduces cardiovascular risk, hypocholesterolemic, anti-hypertensive effect,
reduces atherosclerosis, regulates vascular tone, anti-aging, antioxidant,
anticancerous, neuroprotective
Blueberry Polyphenols, anthocyanins Anti-inflammatory, reduces proinflammatory markers, antioxidant,
scavenging free radical species, chelating metals, reduce oxidative DNA
damage, antilipidemic, antiobesity
Algae Spirulina Neuroprotective, immunostimulatory, reduces cholesterol, antimicrobial,
anticancer, antioxidant, metalloprotective
Sesame Sesamin Antioxidant, reduces blood pressure, antithrombotic, inhibition of
cholesterol absorption, neuroprotective
Curcume Curcumin Antioxidant, anticancerous, anti-inflammatory, immunomodulatory
neuroprotective, inhibits mitochondrial-mediated apoptotic signaling
cascade, decreases lipid peroxidation and mitochondrial dysfunction, BBB
protection
Ginseng Ginseroside-Rg1 Calcium channel antagonist, neuroprotective, reduces BBB damage,
antioxidant, anti-inflammatory, anti-apoptotic and immune-stimulatory
activities

Drugs more suited for short-term ADNES and dietetic compounds more suited for long-term ADNES are shown.
ADNES: Advanced neuroprotection strategy; BBB: Blood--brain barrier; HDL: High-density lipoprotein; HMG-CoA: 3-Hydroxy-3-methylglutaryl-coenzyme A;
LDL: Low-density lipoprotein; MMP: Matrix metalloprotease.

serum lipid levels [17]. Similarly, a study of neuroprotective
effects of NT-020 (nutritional supplement with blueberry
polyphenols, green tea catechins, amino acids and vitamin
D3) in cerebral ischemia model has shown anti-inflammatory
and antioxidant properties related to functional improvement
in animals and cell proliferation in the infarct [18]. In fact, a
diet with 2% blueberry has been related to reduction of
infarct volume and apoptotic cell death [19]. It is important
to understand the mechanisms of action of these compounds;
in this case, the nuclear factor erythroid 2-related factor 2 has
been described as a critical regulator of flavonoids-mediated
protection [20].
Although we tried to differentiate short-term ADNES
drugs and long-term ADNES diet, this is an artificial distinc-
tion and those compounds might of course be useful if they
finally work in both conditions. In fact, components such as
melatonin with an excellent safety profile might be given for
years if shown effective as ADNES [21].
Furthermore, although administration of isolated bioactive
compound can be beneficial, synergies among the food

1140 Expert Opin. Investig. Drugs (2015) 24(9)

 Advanced neuroprotection for brain ischemia: an alternative approach to minimize stroke damage
components may occur producing more benefit than either
treatment alone. Thus, more research is needed to determine
the optimal quantity and food matrix to confer a significant
clinical benefit. Moreover, due to the complexity of the ische-
mic cascade, ideal drugs or bioactive compounds should be
targeting multiple mechanisms of damage in order to suppress
them at the same time. Accordingly, the use of a combined
therapy could be effective.
Finally and following with the idea of rescuing the
acquired knowledge during decades of research for stroke neu-
roprotection, we believe that transgenic models could be a
great tool to develop and demonstrate the effectiveness of
ADNES. Transgenic animals are modified before induction
of ischemia, that is, they are already conditioned before suffer-
ing experimental ischemic brain damage. As an example,
when a KO mouse shows clear reduction of brain infarct fol-
lowing middle cerebral artery occlusion, that gene or pathway
is a theoretical good candidate for ADNES [22]. Understand-
ing how the genetic modification affects the development of
the disease can aid directing efforts on design and synthesis
of new drugs on these targets. This novel approach could be
considered for future neuroprotective drug development for
ADNES.
As an example, a recent study using mice expressing the
human apolipoprotein E4 allele fed on a high-fat diet before
permanent middle cerebral artery occlusion has shown that
mice expressing this protein were more susceptible to sensori-
motor deficits induced by brain ischemia. These deficits are
accompanied by altered astroglial activation, neurogenesis,
cyclooxygenase-2 immunoreactivity and increased plasma
IL-6 [23].
Of course, well-designed studies are necessary to demon-
strate efficacy and safety of this new approach. In our labora-
tory, we will focus in this novel strategy at the experimental
and clinical levels in the coming years.
In conclusion, rescuing the acquired knowledge obtained
over decades on drugs that are effective when given before
experimental brain ischemia and re-profiling those best poten-
tial neuroprotective candidates, in order to apply an ADNES
may be a good approach to develop a successful treatment to
protect the human brain against the ischemic damage.
Expert Opin. Investig. Drugs (2015) 24(9)
2. Expert opinion
ADNES is a novel approach that would try to protect the
brain at risk before damage occurs, to prevent and especially
to minimize brain injury in order to be applied to patients
at high risk for stroke. Although translation from candidate
neuroprotective drugs effective in experimental studies to
stroke patients has systematically failed, some of those treat-
ments which demonstrated only beneficial effects if given
before ischemia induction, discarded for conventional neuro-
protection could be rescued and reprofiled.
We have selected and reviewed a list of candidate treat-
ments (drugs and diets) with the best profile to be used for
ADNES. Strategically investing in nutritional agents (long-
term ADNES) versus neuroprotective pharmacological inter-
ventions (short-term ADNES) has multiple implications. In
this battle between drugs versus food, it is clear that adequate
nutrition strategies offer one of the most effective and least
costly ways to reduce many diseases and their associated risk
factors, especially in long-term treatments. The pharmacolog-
ical therapies could be useful in short-term treatments but
agents with high safety profile could be beneficial also for
long-term treatments. New efforts to design trials that allow
testing ADNES will be required and since high sample sizes
will be required, collaborative efforts will be mandatory. We
believe that applying an advanced neuroprotection on a
specific patient population with high risk of ischemic event,
to prevent or reduce ischemic damage, may yield success to
reduce costs of stroke in the coming decades.
Declaration of interest
The authors have no relevant affiliations or financial involve-
ment with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, con-
sultancies, honoraria, stock ownership or options, expert testi-
mony, grants or patents received or pending or royalties.
1141
M. I. Ayuso & J. Montaner
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Affiliation
Maria Irene Ayuso* & Joan Montaner†
†,
*Authors for correspondence
Neurovascular Research Group, Institute of
Biomedicine of Seville, Hospital Universitario
Virgen del Rocio, Av. Manuel Siurot s/n, 41013,
Seville, Spain
E-mail: mayuso-ibis@us.es; jmontaner-ibis@us.es