Guo et al

Tropical Journal of Pharmaceutical Research December 2013; 12 (6): 1097-1105

ISSN: 1596-5996 (print); 1596-9827 (electronic)
© Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria.
All rights reserved.

Available online at http://www.tjpr.org

http://dx.doi.org/10.4314/tjpr.v12i6.35
Review Article

Pathophysiology and Biomarkers in Acute Ischemic

Stroke – A Review
Yiwang Guo, Pengyue Li, Qingli Guo, Kexin Shang, Dan Yan, Shouying Du*
and Yang Lu*
Department of TCM Pharmaceutics, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102,
China.

*For correspondence: Email: dushouying@263.net, landocean28@163.com; Tel: +86-10-8473-8615; Fax: +86-10-

8473-8611

Received: 17 September 2013 Revised accepted: 14 November 2013

Abstract
Stroke is one of the major causes of death and disability, including ischemic stroke, which
accounts for 85 - 87 % of cases. Currently, there are few treatment options available for
minimizing tissue death following a stroke. Emerging data suggest that biomarkers may help
improve current clinical outcome of stroke. As such, there is a pressing need to understand the
pathophysiology and to explore effective biomarkers following an ischemic brain event. The
pathophysiology of ischemic stroke is complex, and majorly involves excitotoxicity, oxidative
stress, inflammation, blood-brain barrier dysfunction, apoptosis, etc. Several of the biomarkers
are related to these pathophysiologic mechanisms and they may have applications in stroke
prediction, diagnosis, assessment, prognosis or treatment. In this review, we summarized the
pathophysiology of ischemic stroke and some related biomarkers are examined.

Keywords: Ischemic stroke, Pathophysiology, Biomarker, Clinical outcomes

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INTRODUCTION support a clinical diagnosis of stroke, identify

patients at risk of disease, and guide treatment
Stroke is a serious neurological disease and a and prognosis would be valuable [3]. To date,
leading cause of disability worldwide [1]. many ischemic stroke candidate biomarkers
Ischemic strokes constitute 85 – 87 % of all have been identified, but none are currently
cases. Hemorrhagic stroke includes used in clinical practice, so further studies and
spontaneous intracerebral hemorrhage and researches are demanded. The primary
subarachnoid hemorrhage, and account for the objectives of this review are to summarize: (A)
remainder of cases [2].For its enormous clinical, the pathophysiology of stroke and (B) current
social and economic implications, it is urgent to understanding of biomarkers in stroke.
understand the mechanisms and thereby
guiding the diagnosis and therapy of stroke. PATHOPHYSIOLOGY OF ISCHEMIC STROKE
Though neuro-imaging examinations such as
computed tomography (CT) and magnetic Ischemic cerebrovascular disease is mainly
resonance imaging (MRI) are excellent in the caused by thrombosis, embolism and focal
management of stroke patients, biomarkers to hypoperfusion, all of which can lead to a
reduction or an interruption in cerebral blood

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 Guo et al

flow (CBF) that affect neurological function. As Oxidative stress

the brain receives 20% of the cardiac output at
rest [4], it is exquisitely sensitive to ischemia, “Oxidative stress” was first propounded by
such that even brief ischemic periods to neurons Professor Sohal in 1990. It occurs when there
can trigger a complex sequence of events that is an imbalance between production of free
may result in permanent cerebral damage. radicals and endogenous scavenging capacity
of cellular antioxidants. Increasing evidence
Normally, the average CBF in an adult is suggests that reactive oxygen and nitrogen
approximately 50 – 55 ml/100g/min [5]. During molecules are closely linked to tissue injury
brain ischemia, critically reduced CBF causes during acute ischemic stroke [8,9]. Free
-
an inadequate delivery of oxygen and glucose, radicals include superoxide anion (O2 ),
triggering the evolution of stroke hydroxyl radical (OH•), hydrogen peroxide
pathophysiology process. Generally, pathophy- (H2O2), nitric oxide (NO) and so on. Among
siology of ischemic stroke can be said to be in which, O2- is generated earliest, while OH• is
two stages [5,6]: at a CBF of approximately the most toxic.
14±2 ml/100 g/min, the electroencephalogram
becomes isoelectric or evoked responses During ischemic stroke, superoxide anion is the
become abnormal, it’s a region of functionally primarily generated radical through several
impaired but structurally intact tissue, called ways, including mitochondrial electron transport
ischemic penumbra and brain damage here is process [10], xanthine oxidase (XO) system
reversible; when CBF is reduced to which is thought to be a major source for the
approximately 6 ml/100 g/min, the brain damage generation of oxygen free radicals in ischemia
becomes irreversible and results in brain and reperfusion [11,12], and metabolism of
infarction, which is called ischemic core. In this arachidonic acid (AA) through the
regard, salvaging of ischemic penumbra is the cyclooxygenase(COX) pathways. H2O2 is
clinical target for acute stroke therapy. formed from superoxide anion and it is the
source of OH•. NO is generated from L-arginine
The pathophysiology of stroke is extremely by nitric oxide synthases (NOS) which are
complex and involves numerous processes, Ca2+-dependent. NO is very short lived and
including: energy failure, excitotoxicity, oxidative what’s more, it can react with superoxide anion
stress, disruption of the blood-brain barrier to produce peroxynitrite (ONOO-), another
(BBB), inflammation, necrosis or apoptosis etc. highly toxic oxygen species [13]. On the other
hand, antioxidants like superoxide dismutase
Excitotoxicity (SOD), glutathione peroxidase (GPX) and
catalase (CAT) degrade superoxide anion into
Excitotoxicity refers to a sequence of events H2O2, additionally transfer H2O2 into H2O.
induced by excessive accumulation of excitatory Despite these defenses, the brain is vulnerable
amino acids, leading to toxic increases in to oxidative stress resulting from ischemia and
intracellular calcium [7]. As a second reperfusion.
messenger, Ca2+ activates multiple signaling
pathways, which eventually leads to necrosis or Oxidative stress is a significant injury during
apoptosis. Soon after reduction or termination of cerebral ischemia, these free radicals can
+ +
CBF, energy-dependent Na -K -ATP enzyme is attack DNA, proteins and lipids [14], increase
2+
inhibited due to reduced ATP production, Ca , disrupt mitochondrial integrity from which
resulting in turbulence of numerous ions, Cytochrome C is always released to trigger
including Na+, Cl-, Ca2+. These ions can also be apoptosis, cause varying degrees of damage,
interrupted by the overstimulation of 1-amino-3- ultimately result to cell death.
hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA), kainate and N-methyl-d-aspartic acid Inflammation
(NMDA)-type glutamate receptors, all of which
are receptors of glutamate, a major excitatory Several cell types contribute to post-ischemic
neurotransmitter in the brain. Then these cells inflammation, including endothelial cells,
become depolarized, which in turn cause more astrocytes, microglia and neurons [15]. The key
Ca2+ influx and more glutamate release. elements in an inflammation reaction involve
Influxing of numerous ions may result in acute signaling molecules, inflammatory cells,
2+
swelling of cells and additionally, Ca triggers a adhesion molecules and transcriptional
2+
series of events by Ca -dependent enemy and regulators.
ultimately causing cell death.
Increasing amount of Ca2+, oxygen free radical
and ischemia itself can activate astrocytes and

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 Guo et al

microglia to produce proinflammatory cytokines recoverable for some time after the onset of
like interleukin-1 (1L-1), tumor necrosis factor- stroke.
1(TNF-α) and interleukin-1β (1L-1β), as well as
neuroprotective factors, such as erythropoietin, Caspase-dependent mechanism is important
TGFb1, and metallothionein-2 [16]. Most of for activation of apoptosis. It includes the
these cytokines can induce the production of intrinsic pathway, initiated by release of
some adhesion molecules such as selectins (P- cytochrome C from mitochondria and resulted
selectin, E-selectin), immunoglobulin in activating caspase-3; and the extrinsic
superfamily (intercellular adhesion molecule-1, pathway, triggered by activation of cell surface
vascular endothelial adhesion molecule-1) and death receptors and resulted in activating
integrins. Meanwhile interleukin-8 (1L-8), caspase-8[25]. Additionally, Caspase-
monocyte adhesion protein chemistry -1 (MCP- independent mechanism also plays a vital
1) and other chemokines play an important role significant role in apoptosis through PARP/AIF
in the migration of inflammatory cells. With the pathway [25,26]. This is a complex program
help of matrix metalloproteinase (MMP), the that received much attention in recent years.
extracellular matrix is broken down, and
inflammatory cells infiltrate the brain BIOMARKERS IN ACUTE ISCHEMIC
parenchyma. 4-6 h after ischemia onset, STROKE
circulating leukocytes reach the penumbra.
Neutrophils are thought to be the first leukocyte In ischemic stroke, ideal biomarkers should
subtypes involved in inflammation [17]. exhibit characteristics that include sufficient
specificity and sensitivity, early and stable
Blood-brain barrier (BBB) dysfunction release shortly after infarction, predictable
clearance, potential for risk assessment and
Blood-brain barrier (BBB) disruption in acute guidance of therapies, and the ability to be
ischemic stroke varies considerably from15 to quantitatively and rapidly measured by cost-
66 % [18]. Free reactive radicals and effective methodologies [3,27].Many of the
inflammation are major reasons that contribute novel biomarkers of cerebral injury are related
to the damage of the BBB in acute ischemia to the pathophysiology reviewed above, and in
and reperfusion injury. As important proteases clinical scenarios, they may have applications
in brain tissue, MMPs and serine proteases are in stroke prediction, diagnosis, assessment,
essential in the breakdown of the extracellular prognosis or treatment.
matrix around cerebral blood vessels and
neurons, and their action leads to the Coagulation/thrombosis biomarkers
destruction of BBB, brain edema, hemorrhage,
and cell death. So, MMPs are thought to be In most cases, the cause of acute ischemic
direct factors leading to BBB damage [19]. In stroke is atherothrombosis of large cervical or
ischemic stroke, besides pro-inflammation intracranial arteries, or embolism from the heart
reaction, free radicals could also affect the or cerebropetal arteries [28]. In this way,
activities of MMPs both directly and indirectly. molecules involved in coagulation or
thrombosis are associated with ischemic
BBB damage is reported to be biphasic in stroke, including fibrinogen, D-dimer and von
ischemic stroke [20]. 2 hours after the onset of Willebrand factor (vWF), which are most
ischemia, BBB gets a transient opening, which reported in recent years.
may results from oxidative stress that trigger
activation of MMP-9[21] and MMP-2 [22]. This In terms of risk prediction value, fibrinogen was
initial opening is followed 1 to 2 days later by a reported both by Fibrinogen Studies
second, more severe opening which is more Collaboration that plasma fibrinogen level was
complicated and last for several days [18,22]. significantly associated with coronary heart
disease (CHD), stroke, and other causes of
Apoptosis vascular and nonvascular mortality [29], and by
community-based study in Taiwan that a 72%
There are two forms of cell death, necrosis and increase (hazard ratio, 1.72; 1.02 to 2.90) in
apoptosis. In ischemic injury, many brain cells ischemic stroke risk was observed for
undergo apoptosis, which in contrast to individuals with fibrinogen ≥8.79 µmol/L
necrosis, is a relatively orderly process that compared with those <7.03µmol/L, suggested
allows cells to die with minimal damage and fibrinogen is independently predicted future
disruption to neighboring cells [23]. In this way, ischemic risk [30]. Also, D-dimer and vWF are
there is little inflammation or release of genetic reported to be associated with increased risk of
material [2,24] and they are potentially stroke in older men., and these associations

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 Guo et al

were independent of inflammation, especially way to protect neural cells from oxidative
for D-dimer, it is a significant predictor of stroke stress. Clinical researches showed that CAT
in hypertensive men [31]. and GPX activity were significantly higher in
ischemic patients compared to the controls
As a novel biomarker for diagnosing stroke, [38,39], and CAT can be considered as
vWF can present a high sensitivity and adequate marker for positive outcome [39].
specificity when combined with other markers. However, others found GPX activity to be
Lynch et al. [32] analyzed twenty-six significantly lower in stroke patients compared
biomarkers with relation to the ischemic with controls [40,41]. This debate may result
cascade, from which a panel of four (S100B, from the degree of damage by ROS, since
vWF, MMP9, and VCAM) were able to
antioxidant enzymes might be induced by
separate ischemic stroke from controls with
oxidative stress (and therefore their activity
90% sensitivity and specificity. Similarly,
Laskowitz et al [33] reported a panel of five /levels may increase) or else consumed (thus
biomarkers (S100B, vWF, MMP9, B-type NGF decreasing their activity and levels) [42].
and MCP-1) can diagnose stroke with 92 %
sensitivity and 93 % specificity. D-dimer can be SOD, the most studied antioxidant enzyme in
used to distinguish cardioembolic stroke from stroke, whose changes of activity/concentration
other subtypes of ischemic stroke [34]. When in blood were also strongly disputed. Studies
D-dimer was combined with D-dimer/fibrinogen have found the patients’ SOD activity in plasma
ratio, CRP and erythrocyte sedimentation, it [39,40], serum [43] and red blood cells [41] to
can separate large vessel from cardioembolic be significantly lower than the control group,
stroke [35]. Additionally, it is reported that while others found a contrary result of SOD
plasma D-dimer level on admission is activity in red blood cells [44]. Similarly, blood
significantly related to infarction volume and concentration of SOD in stroke patients is
functional outcome in cardioembolic stroke in controversial. This debate may because of the
non-valvular atrial fibrillation patients [36]. three different isoforms of superoxide
dismutase (CuZnSOD, MnSOD and EC-SOD),
Furthermore, Hasan et al [37] found that D- and the different analysis methods [40]. Most
dimer and fibrinogen have prognostic value with studies indicate that SOD concentration and
the results that D-dimer predicted in-hospital activity has a significant correlation with
death (MD 0.67 µgml-1, 95% CI 0.35, 1.00; p = neurological deficit and infarct size.
0.0001), and high fibrinogen levels were
associated with poor outcome at 3 months (MD Stroke patients have been found to have lower
47.90 µgml-1, 95% CI 14.88, 80.93; p = 0.004) levels of retinol, ascorbic acid, uric acid, a-
following ischemic stroke. tocopherol and carotenoids [45,46], but many
studies have demonstrated some inconsistent or
Biomarkers in oxidative stress negative results [47]. While, despite some
different result in certain non-enzymatic
Since direct measurement of reactive free antioxidants, the total antioxidant capacity was
radical (ROS) in the brain is difficult in humans immediately reduced in acute ischemic stroke
because of their transient nature and limitation [48,49]. And some of them have been shown to
of measurements, endogenous antioxidants as have prognosticating value [48,49].
well as several biological substances whose
chemical structure has been modified by free Biomarkers of oxidative products
radicals have been investigated as potential
indirect biomarkers in oxidative stress. ROS can damage lipids, DNA and proteins.
Many metabolites produced during these
Endogenous antioxidants processes can be measured in the serum.

Endogenous antioxidants involve enzymatic Biomarkers of lipid peroxidation

(CAT, GPX and SOD) and non-enzymatic
antioxidants (retinol, ascorbic acid, uric acid, α- The brain cellular membrane lipids are very rich
tocopherol and carotenoid), all of which in polyunsaturated fatty acid side chains, which
consists of the cellular protective antiradical are highly prone to free radical attack resulting
mechanism. in lipid peroxidation that include biomarkers
such as malondialdehyde (MDA), thiobarbituric
Antioxidants catalase (CAT) and glutathione acid-reactive substances (TBARs), lipid
peroxidase (GPX) can dispose H2O2 in a safe peroxides (ROOH) and F2-isoprostanes(F2IPs).
Trop J Pharm Res, December 2013;12 (6):1100
 Guo et al

Plasma levels of MDA, TBARs and lipid Biomarkers of inflammation

peroxides (ROOH) are commonly used
biomarkers of oxidative stress. Several studies Compared to controls, serum levels of IL-1β, IL-
demonstrated that MDA and TBARs levels are 6, IL-8, IL-17, TGF-β, ICAM-1, VCAM-1, E-
higher in cerebral ischemia patients than in selectin, L-selectin, P-selectin, TNF-α, and
controls, and they are correlated with infarct MCP-1 has shown elevation [63-67]. When
size, clinical stroke severity, and patient’s compared to other neurological diseases, serum
outcome [38,50-54]. However, both MDA and level of IL-6, TNF-α, VCAM-1, BDNF, IL-1β,
TBARs lack specificity for measurement of lipid ICAM-1and MMP-2/9 in patients presenting with
peroxidation, because MDA can not only come ischemic stroke were found significantly different
from lipid peroxidaion products, but also from and many of them are correlated with
degradation of endoperoxides [42], and what is neurological deficit and infarct size, such as
more, when react with TBA, other molecules can TNF-α, ICAM-1, BDNF and MMP-2/9 [67]. In
degradated MDA which increase the amount of contrast to the findings from other groups
MDA to react with TBA [55]. [68,69], Sotgiu et al found that IL-6 serum level
showed a significant inverse correlation with
F2IPs are prostaglandin-like products of non- both final neurological impairment and infarct
cyclooxygenase free radical–induced size suggesting that IL-6 is associated with
peroxidation of arachidonic acid , they are neuroprotection rather than neurotoxicity in
thought to be a reliable marker because of its patients with ischemic brain injury [67].
good stability, sensitivityand specificity. They
can be measured in plasma and urine [56]. Kelly TNF-α is a major cytokine with a myriad of
et al. found that F2IPs plasma levels were effects. In an inflammatory reaction, It can be
increased early in ischemic stroke patients expressed by endothelial cells, microglia and
compared to controls [57]. Nevertheless, there astrocytes, and can induce the expression of
are not enough researches about F2IPs. other molecules. Hosomi et al [70] proved that
during an ischemia, TNF-α can inhibit the
Biomarkers of DNA oxidation production of MMPs and reduce brain edema.
While, on the contrary, others thought that
8-hydroxy-2'-deoxyguanosine (8-OHdG), as a TNF-α activated production of MMPs and
product of DNA oxidation, has been widely used increases the inflammatory injury [71]. Such
as an excellent biomarker of oxidative stress different results suggest a complex role of TNF-
[58]. An animal study showed that plasma levels α in inflammatory mechanisms.
of 8-OHdG were increased and significantly
associated with brain content of 8-OHdG [59]. It As an important indicator of inflammation, C-
could be useful to identify patients with high risk reactive protein (CRP) has been studied
of vascular recurrence or vascular death and to extensively. It is an acute phase reactant mainly
identify some particular atherosclerotic plaques produced in liver and rapidly upregulated by
characteristics [60]. In recent years, 8-OHdG inflammatory cytokines. Increased levels of
has appeared to be a promising molecule, there high-sensitivity C-reactive protein (hsCRP)
are still more studies needed to determine levels have been observed in ischemic stroke
whether it can be a useful peripheral biomarker patients [72]. In ischemic stroke, CRP level are
of oxidative damage in stroke patients. correlated with infarct volume and neurological
deficit, and has potential prognostic value for
Biomarkers of protein oxidation poor outcome [73].

There is a lack of studies on biomarkers of Central nervous system (CNS) tissue injury
protein oxidation in ischemic stroke in humans. biomarkers
However, a study on patients with Alzheimer’s
disease and vascular dementia has shown that Ischemic brain injury always cause CNS
measuring the protein carbonyl and the damage, leading to a release of neurons or glia
dityrosine contents of immunoglobulins G (IgG) specific biomarkers such as acidic calcium-
can be feasible not only for its increase binding protein (S100β), glial fibrillary acidic
compared to controls [61], but also for its protein (GFAP), myelin basic protein (MBP),
sensitivity to dietary antioxidant supplementation neuron-specific enolase (NSE).
[62] and a relatively long half-life of 15 days
which making IgG a good short-term marker of Previous studies have agreed that NSE and
oxidative stress [42]. S100β were thought to be of great value for the
Trop J Pharm Res, December 2013;12 (6):1101
 Guo et al

severity of cerebral infarction and prognosis multiple mechanisms, in this way, the detection
estimation in ischemic stroke. Under normal of stroke by use of markers may require multiple
circumstances, content of NSE and S100β is markers to capture simultaneously all processes
very low, while when there is an ischemic injury, underlying the ongoing ischemic event [80].
they are released into the cerebrospinal fluid Clearly there is much work needed before
(CSF) and the blood through the damaged BBB, promising biomarker candidates can be
resulting in an increased levels of NSE and introduced into the clinical practice.
S100β [74]. They are closely correlated with
severity, infarct size and outcome [75,76]. ACKNOWLEDGEMENT

GFAP is a structural protein that is only present This work was supported, in part, by Innovation
in astrocytes, and to a lesser degree, in Team Development Program of Beijing
ependymal cells of the brain. It is released when University of Chinese Medicine (nos. 2011-
cells are disintegrated and the cytoskeletons are CXTD-13 and JYBZZ-JS021).
degraded and its overexpression is specific for
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