Targeting the Brain: Neuroprotection and

Neurorestoration in Ischemic Stroke

Jeffrey L. Saver, M.D., FAHA, FAAN

Many treatments for acute ischemic stroke are vessel and blood based, but
brain-based therapies also hold great promise. Acute neuroprotective
therapies block the molecular elaboration of injury in hypoxic environments.
Prehospital trials of magnesium sulfate are demonstrating the feasibility of
delivering potentially brain-protective agents in the first minutes after stroke
onset. Subacute neurorestoration therapies enhance neuroplasticity and brain
reorganization after stroke. The greatest clinical experience with agents that
can potentiate brain repair has been gained with choline precursors.
Therapies that target the brain in patients with stroke will increasingly
complement and enhance traditional vasotherapeutics.
Key Words: citicoline, magnesium sulfate, neuroprotection, neurorestoration,
stroke.
(Pharmacotherapy 2010;30(7 Pt 2):62S69S)

The therapeutic armamentarium for acute
ischemic stroke may be broadly divided into two
categories: therapies that target the vascular
system and therapies that target the nervous
system. Vascular strategies include recanalization,
prevention of clot propagation, and collateral
enhancement. Neural strategies include acute
neuroprotection and subacute promotion of brain
plasticity and neurorepair. The past 2 decades
have witnessed clinical breakthroughs in vascular
strategies, with multiple therapies demonstrated
to be of proven value (recanalization by intra-
venous fibrinolysis, clot propagation deterrence
by aspirin) or nearly proven value (recanalization
by intraarterial fibrinolysis and mechanical
embolectomy). In contrast, despite ferment in
From the UCLA Stroke Center and Department of
Neurology, David Geffen School of Medicine at UCLA, Los
Angeles, California.
Dr. Saver is a member of the Ferrer Grupo Scientific
Advisory Board and has been reimbursed by Ferrer Grupo
for his contribution.
Based on a satellite symposium at the American College
of Clinical Pharmacy annual meeting held in Anaheim,
California, October 18, 2009, and supported by an
unrestricted educational grant from Ferrer Therapeutics,
Inc., Lake Hiawatha, New Jersey.
For reprints, visit http://www.atypon-link.com/PPI/loi/phco.
For questions or comments, contact Jeffrey L. Saver, M.D.,
FAHA, FAAN, UCLA Stroke Center, 710 Westwood Plaza,
Los Angeles, CA 90095; e-mail: jsaver@ucla.edu.
basic science investigations, neuroprotection and
neurorepair strategies still await translational
success. Nonetheless, a vision widely shared in
the stroke investigational community is that the
stroke therapy of the future will be richly multi-
modal, combining hyperacute neuroprotection,
acute recanalization, clot recurrence prevention,
and subacute neurorestoration (Table 1).
Clinical research in the brain-based ischemic
stroke treatment approachesacute neuroprotec-
tion and subacute neurorestorationis being
reinvigorated by new methodologies and recon-
ceptualizations of prior approaches. In this article,
these promising new developments are illustrated
by examining current research on new uses for
two nutritional supplements, magnesium sulfate
and citicoline.
Neuroprotection
Neuroprotective therapies for patients with
acute ischemic stroke are treatments that enable
brain cells to endure reduced blood flow. 1, 2
Neuroprotective agents interrupt the cellular,
biochemical, and metabolic processes that lead to
brain injury during or after exposure to ischemia
and encompass a wide and continually expanding
array of pharmacologic interventions. As under-
standing of the pathophysiologic complexity of
 NEUROPROTECTION AND NEURORESTORATION IN ISCHEMIC STROKE Saver
Table 1. Evolving Vision for Organized Acute Ischemic Stroke Care
Stage Typical Settings Diagnostic Steps Treatment Strategy
Hyperacute Prehospital, emergency Clinical screens Stabilize penumbra
(02 hrs) department
Early acute Primary stroke center, Rapid CT
(14.5 hrs) emergency department,
intensive care unit
Later acute Comprehensive stroke Multimodal;
(210 hrs) center MRI or CT
Early subacute Stroke unit Complete
work-up
Subacute Rehabilitation unit Functional MRI
CT = computed tomography; MRI = magnetic resonance imaging.
ischemic brain injury and the ischemic cascade
has increased over the past 25 years, the categories
of neuroprotective agents have grown to include
the following: suppressors of neuronal metabolism,
calcium entry blockers, excitotoxic neurotrans-
mission blockers, free radical scavengers, nitric
oxiderelated interventions, apoptosis inhibitors,
hyperpolarization agents that inhibit peri-infarct
depolarization, promoters of membrane repair,
antiinflammatory and anticytokine agents, and
neurotrophic agents.
Although these and additional neuroprotective
classes have been effective in reducing infarct size
in animal stroke models, the record of neuropro-
tective agents in human clinical trials has been
remarkably disappointing. More than 70 neuro-
protective agents have been tested in more than
140 randomized, controlled, clinical trials in acute
ischemic stroke, enrolling over 25,000 patients,
but no agent was unequivocally beneficial in
definitive phase III trials.3 This daunting record
of failure after failure provoked a true Kuhnian
scientific crisis in neuroprotection research around
the turn of the millennium, with many leading
investigators stepping back from studies of
individual agents to identify structural defects in
the research paradigms that reigned both in basic
science laboratories and in translational clinical
trials.1, 4 Valuable lessons learned from previous
trials have yielded distinctive insights into funda-
mental mechanisms of ischemic brain injury, novel
classes of pharmacologic therapies, more appro-
priate designs for neuroprotective clinical trials,
and novel treatment-delivery strategies.
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Treatment Components
Neuroprotective cocktail
Reperfuse rapidly Intravenous thrombolysis
Reperfuse definitively Endovascular recanalization
Reperfusion injury cocktail
Deter reocclusion or Antithrombotics
recurrence Secondary prevention
Enhance neurorepair Nerve growth factors and choline
precursors
Stem cells
Transcranial magnetic stimulation
Neural prosthetics (brain-machine
interface)
Delayed time to start of treatment was a particu-
larly crucial defect that hindered all past human
clinical trials of neuroprotective drugs. Rodent
and nonhuman primate experimental studies
suggest the duration of the therapeutic window
within which neuroprotective intervention can
ameliorate bioenergetic failure in the ischemic
penumbra is very brief, generally less than 23
hours. Most animal studies of neuroprotective
agents initiate therapy within 160 minutes after
ischemia onset. However, although it is within
the first 2 hours of ischemia onset that neuropro-
tective agents in general are beneficial in focal
animal stroke models, no clinical trial of neuro-
protective agent enrolled any substantial cohort
of patients in this time window. Early neuropro-
tective trials permitted initiation of therapy at
lengthy intervals after symptom onsetup to 48
hourswell after the critical period for stabi-
lizing the penumbral region had ended. More
recent trials used shorter entry windows but
continued to treat few patients within the first 1
or 2 hours. An analysis of 5345 patients enrolled
in six neuroprotective trials performed in the
1990s and 2000s showed that only 0.2% of
patients received the study agent in the first hour
after symptom onset and only 1.2% in the second
hour; 6.3% received the agent in the third hour;
and 92.3% were treated beyond 3 hours (Figure
1).5 Devising methods to safely initiate experi-
mental neuroprotective therapies more quickly is
critical if the dramatic benefits of neuroprotective
agents evident in the laboratory are to be achieved
in human stroke victims.
64S Supplement to PHARMACOTHERAPY Volume 30, Number 7, 2010
Prehospital Treatment Delivery
Enrolling patients in the field in acute neuro-
protective trials is a highly promising approach to
the challenge of testing neuroprotective agents in
hyperacute time epochs. In the analogous setting
of acute myocardial ischemia, randomized clinical
trials have shown that paramedic prehospital
diagnosis and initiation of defibrillation and
thrombolytic therapy reduce time to start of
treatment and improve clinical outcome.
Prehospital therapy has been proven beneficial
for other acute neurologic conditions. In status
epilepticus, the Prehospital Treatment of Status
Epilepticus trial showed that paramedic initiation
of anticonvulsants in the field is safe, reliable,
and yields better clinical outcomes than standard
in-hospital therapy.6 In cardiac arrest and global
cerebral ischemia, the Melbourne hypothermia
trial showed benefit of neuroprotective temperature
reduction initiated in ambulances before hospital
arrival.7
In focal ischemic stroke, National Institutes of
Health (NIH) studies have been investigating
magnesium sulfate as a potential field neuro-
protective agent. In a variety of human organ
systems, magnesium plays a regulatory role in
cellular energy metabolism, vascular tone, and
01 hours 23 hours
0.2%
12 hours
1.2% 6.3%
Figure 1. Proportions of patients who received the study agent within the acute time window for study enrollment in a pooled
analysis of 5345 patients in six large neuroprotective trials in the 1990s and 2000s. The area of each box is proportional to the
percentage of patients for each time window. (From reference 5.)
cell membrane ion transport. Magnesium sulfate
has been used as a dietary supplement and intra-
venous therapeutic agent in clinical medicine for
many decades, with a well-established safety
record. Laboratory studies have identified
multiple neuronal and vascular effects of magne-
sium that likely contribute to the potent neuro-
protective effects observed in stroke models.8 In
a wide variety of in vitro systems and animal
models, magnesium has been shown to inhibit
presynaptic release of excitatory neurotransmitters,
noncompetitively block the N-methyl-D-aspartate
(NMDA) receptor, presynaptically potentiate
adenosine, block voltage-gated calcium channels,
suppress cortical spreading depression and
anoxic depolarizations, relax vascular smooth
muscle resulting in vasodilation of large and
small vascular beds and increased cerebral blood
flow, antagonize endothelin-1 and other vaso-
constrictors, and replete an underlying and/or
ischemia-induced magnesium-deficient state.
Moreover, in multiple randomized clinical trials,
magnesium sulfate has shown signals of benefit
for averting brain ischemic injury, including in
cardiac arrest,9 preterm birth,10 cardiac bypass
surgery,11 and aneurysmal subarachnoid hemor-
rhage.12 In an old-fashioned, late-treatmentstart
More than 3 hours
92.3%
 NEUROPROTECTION AND NEURORESTORATION IN ISCHEMIC STROKE Saver
trial in focal stroke, magnesium sulfate demon-
strated a neutral effect, but among patients treated
within the first 3 hours of onset, point estimates
suggested potential benefit.13 Because it is long
off patent protection, magnesium sulfate is
inexpensive and can be tested using innovative
clinical trial methodology unconstrained by
conservative corporate-sponsored development
programs.
The National Institutes of Health FAST-MAG Trials
Prehospital trials of treatments for focal stroke
face several design challenges, including accurate
identification of patients with stroke, rating of
pretreatment stroke severity, elicitation of informed
consent in the field before hospital arrival, and
randomization to appropriate treatment arm.
The Field Administration of Stroke Therapy
Magnesium (FAST-MAG) investigators developed
several novel methods to address these obstacles,
first in a pilot, 20-patient feasibility trial,14 and
then in an ongoing, pivotal, 1700-patient phase
III trial.
Stroke Identification
Paramedics identify patients with stroke using
the Los Angeles Prehospital Stroke Screen (LAPSS),
an 8-item diagnostic inventory that takes 12
minutes to perform, is well validated, and is a
standard part of ambulance personnel training
worldwide.15
Stroke Severity Rating
The Los Angeles Motor Scale (LAMS) is a 05-
point rating of motor deficit severity that is
derived directly from the face, arm, and grip
weakness examination section of the LAPSS.16
When performing the LAPSS, paramedics also
automatically perform the LAMS. Although
simple and rapid, the LAMS is a useful assessment
of stroke deficit severity, correlating well with
concurrently measured 13-item NIH Stroke Scale
(NIHSS)17 scores, and predicting final 3-month
disability, activities of daily living, and neurologic
deficit outcomes nearly as well as the full NIHSS.
Informed Consent Elicitation: Cellular Telemedicine
Most recent prehospital treatment trials have
been conducted for conditions that render
patients incompetent to provide consent, such as
cardiac arrest, under regulations permitting
waiver of explicit consent in emergency
circumstances. In acute stroke, however, many
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patients retain decision-making capacity and
require fully informed consent. Having
paramedics elicit informed consent has the
drawbacks of having nonstroke experts (the
paramedics) answering the patients queries
about informed consent and of diverting
paramedic attention from prehospital duties. In
the cellular telemedicine enrollment system
developed for FAST-MAG, rescue vehicles carry
written informed consent forms and cellular
phones that permit instant connection to on-call
enrolling physician-investigators. 18 The
physician-investigator discusses the trial by
phone with patients or their legally authorized
representatives while paramedics perform
prehospital care duties unimpeded.
Preencounter Randomization
Keep it simple and straightforward (KISS) is an
important principle in prehospital research. In
the potentially chaotic prehospital setting,
complex randomization schemes and multiple
drug source bins have a high risk of leading to
administration of unintended treatment regimens.
To promote reliable and rapid administration of
study agent, the randomized phase III FAST-
MAG trial employs a preencounter randomization
system. Each ambulance is stocked with only
one blinded study kit at a time. When the study
kit is used in a patient, the ambulance is
restocked within 24 hours with the next kit in
that ambulances permuted block treatment
schedule. When given approval to start study
procedures by the enrolling physician-investi-
gator, paramedics can quickly and unambiguously
proceed with administering the sole, prerandomized
kit available in the vehicle.
The FAST-MAG Phase III Trial
Using these techniques, the FAST-MAG phase
III trial has already enrolled more patients in the
hyperacute, under 2-hour period than all
previous acute stroke treatment trials combined.
By the end of 2009, 911 patients had been enrolled,
with a median time interval from when they were
last known to be well to start of study infusion of
46 minutes. 19 Fully 656 patients (72%) were
enrolled within the first hour after onset, and
another 219 (24%) in the second hour. In this
initial cohort, patient demographics are typical
for the stroke population, with an average age of
70 years and 60% of the population male. Stroke-
mimicking conditions have been enrolled at a
low rate of 3%, below the 5% allotted in trial
66S Supplement to PHARMACOTHERAPY Volume 30, Number 7, 2010
sample size projections. The enrolling event was
acute cerebral ischemia in 73% of patients and
intracerebral hemorrhage in 24%.
These preliminary findings indicate that the
FAST-MAG trial is accomplishing several innova-
tions in stroke clinical trials, including being the
first prehospital randomized stroke trial; being
the first treatment trial to enroll a substantial
cohort of patients in first 60 minutes after onset
(the golden hour); and being the first trial
testing neuroprotective therapy delivery in advance
of recanalization therapy, potentially permitting
more brain tissue to still be salvageable when
reperfusion is achieved.
Neuroplasticity and Brain Repair
Few areas in modern neuroscience are as rapidly
evolving and rich with therapeutic promise as
neurorepair and neurorehabilitation. Recent
years have seen tremendous advance in our
understanding of the fundamental neurobiology
of neural network plasticity, axonogenesis,
synaptogenesis, neuronogenesis, and other
mechanisms underlying recovery of function
after stroke. Promising agents already entering
early-stage clinical trials include promoters of
membrane repair, nerve growth factors, stem
cells, laser mitochondrial bioenergetization,
transcranial magnetic stimulation, and neuro-
prosthetics using implanted and noninvasive
brainartificial machine interfaces.20, 21
In contrast with the long record of clinical
trials of acute neuroprotection in ischemic stroke,
few major trials have yet been undertaken that
study pharmacologic and device interventions to
promote brain repair subacutely after stroke.
Many aspects of clinical trial methodology in
neurorestoration are uncertain, including the best
time to initiate treatment, the optimal duration of
treatment, the best target patients, and the most
informative and clinically relevant measures of
treatment success. The most extensive clinical
trial experience with brain repair enhancers has
occurred somewhat inadvertently, in the course
of clinical trials testing putative neuroprotective
compounds. Agents that promote cell repair and
cell growth, such as choline precursors and nerve
growth factors, theoretically may confer both
neuroprotection when administered acutely and
neurorepair enhancement when given subacutely.
As a result, even in the absence of well-formu-
lated theoretical conceptions of brain repair,
clinical trialists testing these compounds often
administered them in both the acute and
subacute period. Many of these studies can be
reconceptualized as early trials of brain repair,
providing greater insight into the meaning and
potential clinical applicability of their findings.
Choline Precursors as Potential Neuroreparative
Agents
Choline precursors are exogenous agents that
are converted to choline in the body and promote
the maintenance, repair, and de novo formation
of cell membrane phospholipids and the neuro-
transmitters acetylcholine and dopamine. A
variety of choline precursor agents have been
tested in clinical trials, including choline, lecithin,
and choline alphoscerate, but by far the largest
experience has been gained with citicoline.22, 23
Citicoline is currently available by prescription
in over 50 countries and is available in the
United States as an over-the-counter nutritional
supplement.
Cell membranes and mitochondrial membranes
are essential for maintaining cellular homeostasis,
activity of membrane-associated enzymes, coupling
of membrane receptor and intracellular signaling,
nerve impulse conduction, and oxidative energy
metabolism. The synthesis of 80% of central
nervous system phospholipids can be altered by
modulating the concentration of citicoline. In
preclinical models, exogenously administered
citicoline promotes rapid repair of injured cell
surface and mitochondrial membranes and
maintenance of cell integrity and bioenergetic
capacity.
Early investigations of citicoline in stroke
models focused on potential acute neuroprotec-
tive effects. Mechanistic studies showed that
citicoline downregulates phospholipases to reduce
apoptotic and necrotic cell death and decreases
free fatty acid release from membranes and the
formation of toxic oxygenated metabolites and
free radicals. In animal models, acute adminis-
tration of citicoline reduced infarct size and
improved behavioral outcomes.
More recent studies have revealed substantial
neuroplasticity-enhancing properties of citicoline.
Because cell membrane phospholipids have a
very high turnover rate, continuous synthesis of
replacement compounds is required to maintain
cell integrity, even in normal circumstances.
Greater demand for phospholipid generation
arises during the perinatal and the subacute
poststroke period to support axonal sprouting,
synaptogenesis, and neuronogenesis. As
formation of citicoline is the rate-limiting step in
 NEUROPROTECTION AND NEURORESTORATION IN ISCHEMIC STROKE Saver
the generation of phosphatidylcholine through
the Kennedy cycle, exogenously administered
citicoline can accelerate phospholipid synthesis
and neural repair.
Two recent animal model studies illustrate the
evidence for a neuroplasticity-enhancing effect of
citicoline. In one investigation, middle cerebral
artery infarcts were made in adult Sprague-
Dawley rats.24 Beginning 24 hours after infarct
onset, beyond the acute neuroprotective period,
animals received either citicoline or saline
placebo for the next 28 days. Animals receiving
citicoline behaviorally showed substantially
greater recovery on tests of sensorimotor inte-
gration (staircase skilled reaching) and asym-
metric motor behavior (elevated body swing
test). Citicoline-treated animals also showed
neuroanatomic evidence of enhanced motor
plasticity and reorganization. Layer V pyramidal
cells in the contralesional motor cortex exhibited
more dendritic branches, greater branch
complexity, and increased density of synaptic
spines in terminal branches in animals receiving
citicoline than in saline controls.
The effect of citicoline on brain plasticity
during the perinatal period was investigated.25 In
the in vitro part of the study, citicoline-treated
culture of somatosensory neurons developed
longer neurites and more branch points, resulting
in a larger arborized field. In the in vivo part of
the study, citicoline was administered to Long
Evans rats daily from conception until 2 months
after birth and pyramidal neurons from
supragranular layers 2 and 3, granular layer 4,
and infragranular layer 5 of somatosensory cortex
were analyzed. Among citicoline-treated animals,
the length and complexity of both apical and
dendritic branches were substantially enhanced.
The clinical trial experience with citicoline in
stroke similarly provides a signal of potential
neuroplasticity-enhancing benefit. In a recent
meta-analysis of 10 randomized clinical trials
enrolling 2279 patients with ischemic or
hemorrhagic stroke, treatment with citicoline
reduced the rate of death or dependency at long-
term follow-up from 67.5% to 57.0% (odds ratio
0.64, 95% confidence interval, 0.540.77;
p<0.00001).23 Although the design of the trials
does not allow definite disambiguation of
neuroprotective and neuroreparative treatment
effects, the time windows for enrollment and
duration of therapy suggest that neuroplasticity
enhancement would have predominated over
acute neuroprotection. In all of the trials, treat-
ment duration was for extended time periods,
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ranging from 10 days6 weeks, subacute periods
during which neuroplasticity enhancement effects
would be expected to occur. Except for one small
trial in patients with hemorrhagic stroke, the
permitted time windows for patient entry were
late. Across all studies, 83% of patients were
enrolled in trials permitting enrollment up to 24
hours after onset and 15% of patients were in
trials permitting enrollment up to 48 hours to 14
days after onset. With these long enrollment
windows, likely very few patients would have
received the study agent in the first 13 hours
after onset, when neuroprotective effects would
be greatest.
Evidence from magnetic resonance imaging
(MRI) in clinical trials of citicoline similarly
supports a predominant neurorepair rather than
neuroprotective effect when the agent is adminis-
tered to patients relatively late after stroke onset.
In a pooled analysis of patients enrolled in two
trials, among 214 analyzed patients, citicoline
reduced the growth of ischemic lesion volume
from study entry to 12 weeks in a dose-
dependent fashion: 82% growth with placebo
versus 34% growth with citicoline 500 mg/day
and 2% growth with citicoline 2000 mg/day
(p=0.015).26 A more fine-grained analysis can be
made of the Citicoline 010 trial, which
randomized patients up to 24 hours from stroke
symptom onset to citicoline or placebo for 6
weeks. 27 The MRI ischemic lesion volume
measures were performed at entry, week 1, and
week 12, permitting separate analysis of early
and late lesion evolution. Strikingly, citicoline
did not attenuate the volume of infarct growth in
week 1 (increase of 28.4 ml for citicoline vs 25.7
ml for placebo), but did enhance lesion reduction
between weeks 1 and 12 (17.2 ml for citicoline
and 6.9 ml for placebo, p<0.01), potentially
consistent with a late neuroreparative effect as
perilesional tissue more vigorously filled in the
infarct bed (Figure 2).27
Additional support for a neuroreparative effect
of citicoline in ischemic stroke comes from a
recent trial comparing a standard and a
prolonged citicoline dosage regimen. Spanish
investigators performed a randomized, open-label
trial to determine if prolonged citicoline therapy
improves cognitive outcome after first ever
ischemic stroke.28 All patients received citicoline
2000 mg/day for 6 weeks, started within 24 hours
of stroke onset. Patients were then randomized
to discontinue therapy or to receive citicoline
1000 mg/day until 6 months after stroke. Among
the 310 patients completing follow-up, neuro-
 68S Supplement to PHARMACOTHERAPY Volume 30, Number 7, 2010
psychologic testing showed fewer abnormalities
in orientation (19.5% vs 29.5%, p=0.042) and
attentional and executive function (33.8% vs
46.8%, p=0.019) after 6 months compared with 6
weeks of treatment. In other cognitive domains,
point estimates also favored the prolonged-
therapy group but the difference between groups
did not reach statistical significance. Of course,
the benefits from therapy extension beyond 6
weeks cannot be attributed to acute neuropro-
tection and are consistent with a neuroreparative
treatment effect.
These tantalizing suggestions of a neurorepara-
tive benefit from citicoline in ischemic stroke,
from both basic science studies and modest-sized
clinical trials, require confirmation. Presently
under way in Europe is a much-needed, large,
pivotal trialthe International Citicoline Trial on
Acute Stroke (ICTUS)that will confirm or
disconfirm the signals of benefit. In ICTUS,
2600 patients with acute ischemic stroke within
24 hours of onset are being randomized to high-
dose citicoline 2000 mg/day or placebo, with
treatment initiated intravenously for the first 3
days, then continued orally until 6 weeks. 29
Among the first 550 patients enrolled, median
time from stroke onset to treatment start was 4.5
hours, suggesting that ICTUS results will reflect
combined neuroprotective and neuroreparative
effects of citicoline. Additional studies of citico-
lines effects specifically on late brain reorgani-
zation are warranted, including functional MRI
70
60
50
Lesion Volume (ml)
40
30
20
10
0 neuronal and vascular effects of magnesium
Baseline Week 1 Week 12
Placebo Citicoline
Figure 2. Evolution of lesion volume among 81 patients
randomized to citicoline or placebo within 24 hours of onset
of ischemic stroke. Absolute change from baseline to week 1
did not significantly differ between treatment groups, but
from week 1 to week 12, reduction in lesion volume was
greater in the citicoline group (17.2 ml vs 6.9 ml, p<0.01).
(From reference 27.)
and voxel-based morphometry MRI investigations,
trials testing whether citicoline may potentiate
constraint-induced recovery techniques in
patients with chronic stroke, staggered-start trials
comparing acute versus subacute initiation of
citicoline (disentangling acute neuroprotection
from subacute neurorepair), and staggered-end
trials comparing standard versus prolonged
continuation of therapy (determining the
duration of the subacute window during which
neuroplasticity enhancement may be effective).
Conclusion
Therapies targeting the neural parenchyma
show great promise as synergistic complements
to reperfusion therapies for acute ischemic
stroke. As demonstrated with magnesium
sulfate, neuroprotective agents can be started in
the field hyperacutely, before hospital arrival,
brain imaging, and reperfusion therapy, poten-
tially freezing the ischemic penumbra and
delivering to hospital-based interventionalists
greater volumes of salvageable brain to save. In
patients for whom acute brain resuscitation
strategies provide insufficient relief, subacute
neuroplasticity-enhancing therapies will soon (or
perhaps with citicoline already do) facilitate brain
repair and improved functional outcomes. With
these approaches, it may be foreseen that physi-
cians treating stroke in the future will plumb the
depths of the mind literally and metaphorically,
preserving threatened parenchyma with neuro-
protective agents, reopening blocked pipes
with lytics and mechanical devices, and stimu-
lating brain plasticity and recovery with
neuroreparative agents.
Main Points
Brain-based therapies for acute ischemic stroke
hold great promise. Neuroprotective therapies
block the molecular elaboration of injury in
hypoxic environments, and neurorestoration
therapies enhance neuroplasticity and brain
reorganization after stroke.
Laboratory studies have identified multiple
that likely contribute to the potent neuro-
protective effects observed in stroke models.
In clinical trials, magnesium sulfate has shown
signals of benefit for averting brain ischemic
injury.
Choline precursors and nerve growth factors,
which promote cell repair and growth, may
confer neuroprotection when administered
 NEUROPROTECTION AND NEURORESTORATION IN ISCHEMIC STROKE Saver
acutely and neurorepair when given subacutely.
In animal stroke models, acute administration
of citicoline reduced infarct size and improved
behavioral outcomes. More recent studies have
revealed substantial neuroplasticity-enhancing
properties of citicoline.
Neuroprotective agents such as magnesium
sulfate can be administered in the field, before
hospital arrival; subacute neuroplasticity-
enhancing therapy with citicoline can facilitate
brain repair and improve functional outcomes.
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