Ischemic Cerebral Damage : An Appraisal of Synaptic Failure

Jeannette Hofmeijer and Michel J.A.M. van Putten

Stroke. 2012;43:607-615; originally published online December 29, 2011;

doi: 10.1161/STROKEAHA.111.632943
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 Ischemic Cerebral Damage
An Appraisal of Synaptic Failure
Jeannette Hofmeijer, MD, PhD; Michel J.A.M. van Putten, MD, PhD

Abstract—In the human brain, ⬇30% of the energy is spent on synaptic transmission. Disappearance of synaptic activity
is the earliest consequence of cerebral ischemia. The changes of synaptic function are generally assumed to be reversible
and persistent damage is associated with membrane failure and neuronal death. However, there is overwhelming
experimental evidence of isolated, but persistent, synaptic failure resulting from mild or moderate cerebral ischemia.
Early failure results from presynaptic damage with impaired transmitter release. Proposed mechanisms include
dysfunction of adenosine triphosphate-dependent calcium channels and a disturbed docking of glutamate-containing
vesicles resulting from impaired phosphorylation. We review energy distribution among neuronal functions, focusing on
energy usage of synaptic transmission. We summarize the effect of ischemia on neurotransmission and the evidence of
long-lasting synaptic failure as a cause of persistent symptoms in patients with cerebral ischemia. Finally, we discuss the
implications of synaptic failure in the diagnosis of cerebral ischemia, including the limited sensitivity of diffusion-weighted
MRI in those cases in which damage is presumably limited to the synapses. (Stroke. 2012;43:607-615.)
Key Words: brain metabolism 䡲 cerebral ischemia 䡲 synaptic failure

T he human brain is metabolically expensive. Although it

represents only 2% of the body weight, it accounts for
20% of oxygen consumption and 25% of glucose utiliza-
spent on synaptic transmission.7 Disappearance of synaptic
activity is the earliest consequence of cerebral ischemia8 and
failure of synaptic transmission has been proposed to account
tion.1,2 Cerebral ischemia is a pathological condition in which for electric silence in the penumbra.3,6,8 –10 The changes of
blood flow to the brain is insufficient to meet these metabolic synaptic function are generally assumed to be reversible. It is
demands, causing a loss of neuronal function and viability. even hypothesized that suppression of functional synaptic
Ischemia may be focal if a brain artery is occluded or global, activity is a compensatory mechanism to balance oxygen
for example, after cardiac arrest. supply and consumption in favor of maintaining resting
In the 1950s, the concept of perfusion thresholds was potentials and preserving the neurons’ structural integrity.11
introduced.3 It was shown that functional activity became However, the observation that adenosine triphosphate (ATP)
impaired with moderately reduced perfusion (14 –35 mL/100 concentrations decline first in synaptic as compared to other
g/min), along with electroencephalographic and evoked po- slice regions, even before the occurrence of changes in
synaptic activity,12 suggests failure as a result of energy
tential disturbances, whereas loss of ion gradients across the
exhaustion rather than energy saving.
plasma membrane and subsequent cell swelling occur at
Here, we review energy distribution among neuronal func-
lower perfusion levels ⬇4.8 to 8.4 mL/100 g/min (Fig-
tions, focusing on energy usage of synaptic transmission. We
ure 1).3–5 In focal brain ischemia, the brain tissue that is
summarize the effect of ischemia on neurotransmission and
perfused in the flow range between these 2 levels is now
the evidence of long-lasting synaptic failure as a cause of
called the penumbra.6 The penumbra is considered structur- persistent symptoms in patients with cerebral ischemia. Fi-
ally intact and viable, but functionally silent. The dysfunction nally, we discuss the possible implications of synaptic failure
is, in principle, reversible by restoration of blood flow. in the diagnosis of cerebral ischemia.
However, if oxygen and glucose are not resupplied in time,
irreversible damage occurs. Metabolic Demands in the Brain
Knowledge on the distribution of energy usage among Approximately 25% of the brain’s energy expenditure com-
different neuronal activities may contribute to understanding prises basic cellular activities, such as protein synthesis,
the successive loss of cell function and cell damage in intracellular transport, and mitochondrial proton leakage.13,14
cerebral ischemia. In the human brain, ⬇30% of the energy is The remaining 75% is required for signaling processes. These

Received July 18, 2011; accepted October 19, 2011.

From the Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands; Department of Clinical Neurophysiology, Medisch Spectrum
Twente and Clinical Neurophysiology at MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The
Netherlands.
Correspondence to Jeannette Hofmeijer, neurologist, Department of Neurology, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, The
Netherlands. E-mail [email protected]
© 2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.632943

607
608 Stroke February 2012

subsequently transported into the mitochondria and converted

into acetyl-CoA to enter the tricarboxylic acid cycle. In
subsequent steps of the tricarboxylic acid cycle, oxidative
phosphorylation produces an additional 30 mol ATP per mol
of glucose.22 Thus, the energetic value of mitochondrial
oxidative phosphorylation is obvious. A high density of
mitochondria has been found around the synaptic cleft.23,24
Besides the fact that critical steps in the metabolism of the
neurotransmitters glutamate and GABA are located in the
mitochondrial tricarboxylic acid cycle,25 this high concentra-
tion of mitochondria probably reflects high energy
consumption.
Most observations on synaptic transmission concern glu-
tamatergic neurotransmission and are extrapolated because
excitatory neurons outnumber inhibitory neurons with a
Figure 1. Cerebral blood flow related to EEG findings and viabil- factor of 9 to 1, and 90% of the synaptic transmission is
ity of neurons. CBF, cerebral blood flow; EEG,
electroencephalography. glutamatergic.18,26 Energy needed for glutamatergic signaling
comprises: (1) presynaptic ion fluxes and release of gluta-
may be further subdivided in maintaining a “communicable mate; (2) postsynaptic actions of glutamate; and (3) glutamate
resting state” and ”active signaling.” The “communicable recycling (Figure 2). Calculations on the energy needs of
resting state” depends on a transmembrane resting poten- these components were calculated and published by Attwell
tial resulting from ion gradients across the semipermeable and Laughlin in 2001.13 The 3 steps can be summarized as
neuronal membranes. Ion gradients require proper functioning of follows.
various energy-dependent ion pumps.15,16 “Active signaling” First, the presynaptic action potential triggers calcium
comprises synaptic neurotransmission, action potential gen- influx by the opening of voltage-dependent calcium channels,
eration, and propagation. In rodents, active signaling accounts resulting in a strong increase in the intracellular calcium
for ⬇87% of energy consumption, half for synaptic processes concentration. This is quickly followed by active extrusion of
and half for propagation of action potentials.13 In humans, the calcium by the 3Na⫹/Ca2⫹ exchanger, requiring ⬇12 000
density of neurons is 3-fold to 10-fold lower than in rodents ATP per vesicle released.27 Vesicle release and recycling are
with an unchanged density of synapses, implying a 3-fold to not completely understood. Phosphorylation of synaptic pro-
10-fold higher number of synapses per neuron.17 The ex- teins, called synapsins, plays a regulating role. Under resting
pected share of synaptic consumption relative to other conditions, synapsins bind synaptic vesicles to the cytoskel-
energy-dependent processes therefore is probably also higher. eton. Phosphorylation is induced by the increase in intracel-
Glucose is the main substrate for cerebral energy produc- lular calcium and results in the undocking of vesicles from
tion.18 –21 After transport across the blood– brain barrier and the reserve pool, allowing them to move to the membrane and
cell membrane, glucose is converted into pyruvate via the release their neurotransmitter.28,29 The complete process of
anaerobic glycolytic pathway in the cytosol. This results in vesicle release and recycling needs ⬇1000 ATP per vesicle,17
the production of 2 mol ATP per mol of glucose. Pyruvate is in which membrane fusion costs ⬇400 ATP per vesicle.30

Figure 2. Adenosine triphosphate usage of the

different steps of synaptic transmission for one
vesicle of released glutamate. Data based on
Attwell and Laughlin 200113
 Hofmeijer and van Putten Synaptic Failure in Ischemia 609

The total presynaptic energy consumption, therefore, is could be demonstrated up to 4 weeks after the ischemic insult
13 000 ATP/vesicle. and was considered permanent.48 –51
Second, postsynaptic actions of glutamate comprise the Sun et al43 studied the effect of brief hypoxia on the rat
induction of ion fluxes with Na⫹ influx through non-N- hippocampus in vitro as well as in vivo. Two minutes of
methyl-D-aspartate (NMDA) receptor channels, and Na⫹ and hypoxia caused a synaptic arrest with elimination of excit-
Ca2⫹ influx through NMDA receptor channels. Calcium is atory postsynaptic potentials in vitro. During the synaptic
actively extruded by 3Na⫹/Ca2⫹ and sodium by 3Na⫹/2K⫹ arrest, no depolarization was measured, indicating that the
exchange, at a mean cost of ⬇67 000 and 70 000 ATP arrest could not result from membrane depolarization. Fur-
molecules per vesicle of glutamate, respectively. Further- thermore, local application of L-glutamate caused a postsyn-
more, glutamate metabotropic receptors can actively activate aptic response, indicating that the arrest was caused by failure
phospholipase C to generate triphospho-inositol (a second of the presynaptic neuron. Moreover, they found long-lasting
messenger, also called IP3, which releases calcium influx posthypoxic impaired learning and memory in rats according
from intracellular stores), alter cAMP production (which to a water maze test, without evidence of cellular damage on
modulates neuronal excitability), or modulate calcium chan- histological examination, consistent with a transmission de-
nels. The energy costs of all these processes have been fect without structural neuronal damage.43
estimated at 3000 ATP per released vesicle of glutamate. Bolay et al41 found a restored axonal conduction, but a
Third, the released glutamate is taken-up mainly into lasting impairment of cortical synaptic transmission by means
astrocytes, driven by the cotransport of Na⫹ and H⫹ and the of intracortically evoked potentials in the rat motorcortex
countertransport of K⫹. The Na⫹, K⫹, and H⫹ are actively after transient focal ischemia in vivo. In a later study, they
pumped back by Na⫹/K⫹ and Na⫹/H⫹ pumps, respectively.31 showed a long-lasting defect of synaptic transmission in the
The glutamate taken-up is partly converted into glutamine.32 penumbral region after transient middle cerebral artery oc-
Glutamine leaves glia and enters neurons passively, driven by clusion in rats. An intact response of postsynaptic neurons to
the glutamine concentration gradient.33 Finally, glutamate is glutamate as well as a preserved function of pyramidal cells
repackaged into vesicles powered by vesicular H⫹ ATPase.34 to generate action potentials matched their hypothesis of
For recycling of 1 vesicle of glutamate, the sum of these presynaptic failure. They searched for the exact site of the
processes has been calculated to cost ⬇11⫻103 ATP.13,17 In presynaptic defect by examining phosphorylation of
sum, the total energy consumption associated with the release synapsin-1 by means of an antibody detecting the phospho-
of a single vesicle of glutamate is 164 000 ATP. Postsynaptic form of this protein. They found decreased phosphosynapsin
actions of glutamate consume the largest portion (85%). immunoreactivity, suggesting a permanent ischemia-induced
Presynaptic ion fluxes, glutamate excretion, and vesicle phosphorylation defect.42
recycling consume a share of 8%, whereas glutamate recy- Evidence of failure of presynaptic calcium channels as a
cling uses only 7%.13 cause of presynaptic hypoxic failure dates from the 1980s and
For mouse pyramidal cells, the total cost of synaptic 1990s and has been demonstrated by voltage clamp experi-
signaling by a single pyramidal cell has been estimated, ments52–54 and measurements of extracellular in intracellular
assuming 8000 output synapses, a mean firing rate of 4 Hz, calcium concentrations in vitro.55–57 Elevated intracellular
and a vesicle release probability of 0.25. This results in 2000 Ca2⫹ levels result from hypoxia-induced inflow from outside
vesicles of glutamate per action potential, giving an estimated and release from internal stores. Elevation of intracellular
total synaptic cost of 3.28⫻10 8 ATP/neuron/action Ca2⫹ inactivates voltage-gated calcium channels, thus ham-
pering transmitter release.58,59 Moreover, decay of the cal-
potential.17
cium gradient between intracellular and extracellular space as
Synaptic Failure in Ischemia a result of calcium inflow probably diminishes calcium
In the 1960s, depression of excitatory synaptic transmission currents that initiate transmitter release.52
in hypoxic circumstances was shown in different regions of Other, provisionally unproven, mechanisms of presynaptic
the brain.8,35,36 Thereafter, changes in synaptic responses after failure include failure of action potential propagation from
variable periods of hypoxia or ischemia have been shown the (myelinated) axon to the (unmyelinated) terminal
frequently in vitro37,38,39,40 and in vivo,41,42,43 and several branches and focal depolarization of presynaptic buttons.
causes of presynaptic and postsynaptic ischemic failure have Depletion of available neurotransmitter is unlikely the cause
been postulated. of failure, because adding glutamine to hypoxic hippocampal
slices does not alleviate the synaptic block.60
Evidence of Presynaptic Failure Selective structural damage of presynaptic components as
Most evidence upholds the assumption that early hypoxic a result of transient focal ischemia has been shown in a few
synaptic failure is primarily a result of presynaptic malfunc- studies and comprises isolated loss of synaptic buttons61 and
tion and associated with impaired transmitter release. This a decreased density of presynaptic projections.62 Elevated
suggestion is based on a variety of observations of decreased levels of proteins involved in synaptogenesis, such as growth-
postsynaptic potentials evoked by stimulation of afferent associated protein63,64 or synaptophysin,65 and an increase in
fibers in the presence of intact responses to exogenous the density of dendritic spines within hours to days after brief
glutamate or other postsynaptic receptor agonists44 – 47 or ischemia62,66,67 suggest efforts to normalize these structural
intact spontaneous miniature excitatory postsynaptic poten- changes. However, complete functional recovery is mostly
tials in vitro.48 In several studies, this transmission defect not achieved.68
610 Stroke February 2012

Evidence of Postsynaptic Failure receptor and simultaneously the postsynaptic neuron is depo-
In early studies, a decrease of postsynaptic excitability has larized to remove Mg2⫹ from the channel. Once achieved,
been attributed to anoxic depolarization of the postsynaptic this leads to a long-lasting increased synaptic strength.
membrane.35,69 Later, a decreased membrane function was Memory is thought to be encoded by modification of synaptic
ascribed to a slight focal postsynaptic hyperpolarization strength, and LTP is thought to be one of the mechanisms
occurring just before the massive hypoxic depolarization,70,71 underlying the process of learning.91,92 In hippocampal neu-
resulting from an enhanced K⫹ conductance.52,71 As in rons, LTP of synaptic transmission can be induced by
presynaptic failure, an increased intracellular calcium con- high-frequency stimulation of Schäffer collaterals or per-
centration resulting from inflow from outside and release forant fibers and leads to a sustained increase of excitatory
from internal stores probably plays a key role, either as the postsynaptic potentials amplitude.
initial event or as the final common path.52 Opposite effects of hypoxia on LTP in the hippocampus
The postsynaptic density is a protein-dense region attached have been described. Diminishment of high-frequency
to the postsynaptic membrane. Hundreds of different proteins stimulation-induced LTP has been shown in rat hippocampal
have been identified here with different functions in the slices and comes together with membrane failure.93 Anoxia-
cascade of signal transmission, including the postsynaptic induced LTP leads to a persistent enhancement of glutama-
receptors themselves and many signaling molecules.72 Detri- tergic excitatory postsynaptic potentials amplitude, without a
mental effects of transient focal ischemia on specific subcom- change of the resting potential of the postsynaptic mem-
ponents of the postsynaptic density have been found by brane.44,94 –97 The increased excitatation is selectively related
several authors in rat hippocampal slices. The demonstrated to NMDA receptor responses and results from a reduction of
defects strongly depended on the a priori hypothesis and the the ability of Mg2⫹ to induce a voltage-dependent blockade
resulting research method. Deleterious effects on both mor- of the response.96,98 However, the exact mechanism is not
phological appearance73 and protein interactions have been understood.99 It has been hypothesized that structural modi-
shown.74 –78 fications of synapses over the course of minutes or hours after
The effect of ischemia on the NMDA receptor is dual. Mild mild ischemia may play a role, such as enlargement of
ischemia causes overactivation associated with unregulated existing spines and filopodia.100,101 Anoxia induced LTP also
calcium inflow and consequent delayed neuronal death, has been called pathological plasticity,102 because the result-
whereas severe ischemia causes inactivation with transmis- ing hyperexcitability is associated with delayed neuronal cell
sion failure.79 Synaptic failure as a result of NMDA receptor death, resulting from increased calcium uptake.103,104 In-
inactivation has been shown repeatedly in vitro80,40 and in creased excitability as a result of LTP has been associated
vivo,79 and it has been associated with increased phosphory- with poststroke epileptic seizures.105,106
lation of the receptor.81,82 However, coexisting damage of
Selective Vulnerability
presynaptic functions and neuronal damage were not un- Hippocampal pyramidal and cerebellar Purkinje cells are
equivocally refuted in any of the studies examining postsyn- relatively sensitive for oxygen or glucose deprivation, fol-
aptic effects. Moreover, overactivation of the postsynaptic lowed by pyramidal cells of the neocortex.107 The exact cause
neuron, which is considered an early sign in mild ischemia, is of this high sensitivity remains unclear. However, both
probably partly caused by increased levels of excitatory pyramidal cells and Purkinje cells are large and have substan-
amino acids (mainly glutamate) in the synaptic cleft40,83,84 tial connectivity, which may play a role. In the hippocampus,
because of a coexisting presynaptic effect. astrocytes are relatively sensitive for oxygen and glucose
Structural degeneration or isolated focal swelling of post- deprivation as well.108
synaptic dendrite spines without neuronal or axonal damage Furthermore, synaptic disinhibition fails before synaptic
have been identified in vivo as characteristic early features of excitation. This does not result from selective failure of
cerebral ischemia.73,74,85– 88 In cortical neurons that survived GABAergic transmission: inhibitory synapses are probably
global ischemia, a reduction in dendrite complexity and loss even more resistant to hypoxia then excitatory synapses.109,46
of dendritic spines was observed.89 Similar changes can be The inhibition is caused by failure of the excitatory input to
seen after brain cell injury as a result of excessive glutama- inhibitory interneurons, leading to silencing of inhibitory
tergic stimulation, one of the pathways linking ischemia and interneurons.110 This may contribute to excitotoxicity with
neuronal injury.90,85 delayed cell death. Also, it may lead to abnormal excitatory
synchronicity after cerebral ischemia, manifesting as electro-
Effects on Synaptic Plasticity
encephalographic status epilepticus in posthypoxic encepha-
Under physiological conditions, synaptic strength is not
lopathy after cardiac arrest.111
fixed, but can be modulated. Long-term potentiation (LTP) is
a form of synaptic plasticity to increase synaptic strength. It Imaging of Ischemic Damage in Clinical Practice
leads to an increased postsynaptic cell’s sensitivity to signals Brain imaging in ischemia may focus on structural changes,
received from the presynaptic cell and is usually achieved by perfusion abnormalities, or both. Diffusion-weighted MRI
means of synchronous stimulation. LTP contributes to in- (DWI) is the most sensitive commonly available technique
creased strength of NMDA receptor-dependent signal trans- measuring tissue damage in acute cerebral ischemia.112–116
mission. The NMDA receptor is a nonspecific cation channel, DWI provides signal contrast based on differences of random
which is blocked by Mg2⫹ at physiological levels. It only (Brownian) motion of water molecules or diffusion capac-
opens if the presynaptic neuron emits glutamate to bind to the ity.114 If the diffusion capacity is restricted, then signal
 Hofmeijer and van Putten Synaptic Failure in Ischemia 611

intensity increases. Diffusion restriction can be visible within limited transmitter release in ischemia remain unknown.
minutes after the onset of cerebral ischemia.117 It is thought to MRI-based measurements of cerebral ischemic damage in the
reflect intracellular (cytotoxic) edema, resulting from failure clinic focus on structural changes of neurons. We propose
of energy-dependent transmembrane Na⫹/K⫹ pumps.52 Sig- that damage limited to the synapses may play a role in
nal changes on T2-weighted and fluid-attenuated inversion ischemic damage without DWI changes. This is supported by
recovery MRI are based on prolonged T2 relaxation and various changes in the electroencephalography.
reflect interstitial edema. These usually become visible 3 to 8 Not just acute cerebral ischemia results in neuronal dys-
hours after the onset of focal ischemia.115,118,119 function. For instance, cognitive impairment has been recog-
Many of the initial case series reported nearly 100% nized in patients with chronic mild cerebral ischemia. In
sensitivity for DWI in the acute stage of focal cerebral patients with heart failure, cognitive impairment occurs with
ischemia. Meanwhile, several cases of DWI-negative stroke an odds ratio of 1.6, as compared with subjects without heart
have been reported.120 –123 The sensitivity of DWI for the failure, and is attributed to chronic hypoperfusion.131,132
diagnosis of ischemic stroke is now estimated to be 80% to Energy depletion is associated with decreased brain size,133
90%.115 False-negative MRI results are usually attributed to and in patients with cardiac failure medial temporal lobe
infarct size in relation to spatial resolution.120 –123 However, atrophy, but not T2 white matter hyperintensities, it is
different observations of permanent ischemic neurological associated with hypotension134 and impaired cognitive func-
disturbances without DWI changes suggest functional dam- tioning.135 Furthermore, in a large prospective study in
age with intact structural neural integrity. In particular, in patients with chronic obstructive pulmonary disease, hypox-
global cerebral ischemia severe and extensive ischemic dam- emia was the only parameter associated with the occurrence
age may occur in the absence of DWI abnormalities. Al- of cognitive failure after multivariable regression analysis
though the amount of brain tissue with reduced ADC values and treatment with supplemental oxygen decreased the risk136
is inversely related to clinical outcome in comatose patients matching functional damage without structural lesions.
after cardiac arrest,124 –127 lack of any relevant lesions on DWI An increased understanding of the pathophysiology of
or T2-weighted MRI in the acute, subacute, and chronic synaptic failure could serve the development of clinical
period have been found repeatedly.124,125,128,129 This absence applicable diagnostics to visualize transmission failure. Mo-
of DWI abnormalities did not exclude severe functional lecular imaging, for example, by means of nuclear imaging
deficits. In a recent prospective cohort study in patients with techniques directed toward proteins associated with neu-
global cerebral ischemia after cardiac arrest, 3 out of 15 rotransmission, such as postsynaptic receptors, may increase
patients with poor neurological outcome had no DWI abnor- possibilities to qualify events in the ischemic cascade.137,138
malities at all after 2, 7, and 14 hours, respectively.126 In MRI-based molecular imaging of synaptic processes would
another patient with severe global ischemic brain injury need augmentation of the intrinsic low sensitivity. However,
affirmed by autopsy findings, no DWI abnormalities were the combination of anatomic and functional information
found 6 hours after the onset of ischemia.124 Similar findings could contribute to the estimation of the severity of ischemic
have been reported in patients with focal ischemia. In a recent changes and prognosis with regard to standing deficit. Spe-
prospective study in 246 patients with a clinical diagnosis of cific magnetic resonance spectroscopy techniques already
ischemic lacunar or minor cortical stroke, 60 patients did not allow quantitative studies of cerebral energy metabolism and
show the infarct on MRI performed at 4 to 27 days after the neurotransmission.139
insult.122 The mechanism of functional failure remains un- Knowledge of ischemic synaptic failure may gain even
clear in these patients. We propose that synaptic dysfunction wider application, if it could contribute to the implementation
may play an important role. This is supported by electroen- of particular treatments. Specific defects of neurotransmis-
cephalography findings. In patients with postanoxic enceph- sion have been associated with secondary damage through
alopathy after cardiac arrest, a variety of electroencephalog- uncontrolled transmitter release.40,83,84 Targeted neuroprotec-
raphy disturbances can be observed that reflect diffuse tive therapy could prevent secondary damage in adequately
synaptic disturbances.111 Moreover, bilateral absence of me- selected patients. Patient selection for potentially dangerous
dian nerve somatosensory-evoked potentials is a strong treatments, such as aggressive recanalization therapy or
marker of poor outcome after cardiac arrest130 in which neuroprotective cooling, could be guided by knowledge of the
somatosensory-evoked potentials reflect thalamocortical glu- mechanisms and reversibility of synaptic failure. Patients
taminergic synaptic functioning. with cognitive disturbances resulting from transmission
failure attributable to chronic ischemia/hypoxemia could
Discussion benefit from treatment to enhance cerebral perfusion or
There is overwhelming experimental evidence of isolated, but blood oxygenation.
persistent, synaptic failure resulting from mild or moderate In the past decennia, there has been much interest in
cerebral ischemia. Early synaptic failure results from im- neuroprotection after ischemic stroke. Various agents have
paired transmitter release, for which different mechanisms been tested to antagonize injurious biochemical and molecu-
have been proposed, such as dysfunction of presynaptic lar events, such as calcium channel blockers, glutamate
ATP-dependent calcium channels52 and a disturbed docking antagonists, and GABA agonists.140 There has been a remark-
of glutamate containing vesicles attributable to impaired able discrepancy between the results of experimental studies
phosphorylation.42 Postsynaptic processes consume most en- and clinical trials. Many studies in animal models showed
ergy in neurotransmission, and the exact mechanisms of that protection of ischemic brain by specific neuroprotective
612 Stroke February 2012

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