original article

Wien Klin Wochenschr

DOI 10.1007/s00508-015-0742-6

Serum antioxidant enzymes activities and oxidative

stress levels in patients with acute ischemic stroke:
influence on neurological status and outcome
Aysel Milanlioglu · Mehmet Aslan · Halil Ozkol · Vedat Çilingir · Mehmet Nuri Aydın · Sevdegül Karadas

Received: 4 September 2014 / Accepted: 19 January 2015

© Springer-Verlag Wien 2015

Summary malondialdehyde (MDA) levels, superoxide dismutase

Background  Oxidative stress is well believed to play a (SOD), glutathione peroxidase (GSH-Px), and catalase
role in the pathogenesis of acute ischemic stroke. Reports activities were measured spectrophotometrically.
on antioxidant enzyme activities in patients with stroke Results  Serum MDA levels were significantly higher
are conflicting. Therefore, the aim of this study was to in acute ischemic stroke patients within 24 h after stroke
investigate serum antioxidant enzyme activities and oxi- onset than controls (p < 0.05), whereas serum catalase
dative stress levels in patients with acute ischemic stroke activity was significantly lower (p < 0.05). There were no
within 1st, 5th, and 21st day after stroke onset and also significant differences in GSH-Px and SOD activities.
the relationship between these results and the clinical Serum catalase and SOD activities were significantly
status of patients. lower in fifth day than those of controls (both, p < 0.05)
Methods  The current study comprised 45 patients with but GSH-Px activity and MDA levels did not change
acute ischemic stroke and 30 healthy controls. Serum (p > 0.05). Serum SOD activity was significantly lower in
21st day compared to SOD activity of controls (p < 0.05)
Assist. Prof. A. Milanlioglu () · Assist. Prof. V. Çilingir ·
but MDA levels, GSH-Px, and CAT activities did not
Dr. M. Nuri Aydın change significantly.
Department of Neurology, Faculty of Medicine, Yüzüncü Yıl Conclusions  Our study demonstrated that acute isch-
University, emic stroke patients have increased oxidative stress and
65000 Van, Turkey decreased antioxidant enzymes activities. These findings
e-mail: ayselmilanlioglu@yahoo.com indicated that an imbalance of oxidant and antioxidant
Assist. Prof. V. Çilingir status might play a role in the pathogenesis of acute isch-
e-mail: vedatcilingir@yahoo.com emic stroke.
Dr. M. Nuri Aydın
e-mail: nuriaydin571@gmail.com Keywords  Acute ischemic stroke · Catalase · Superoxide
dismutase · Oxidative stress
Assoc. Prof. M. Aslan
Department of Internal Medicine, Faculty of Medicine, Yüzüncü Yıl
University,
65000 Van, Turkey
Introduction
e-mail: m.aslan301@mynet.com
Stroke is the third cause of mortality in many countries,
Assoc. Prof. H. Ozkol and a major cause of severe physical disability, particu-
Department of Medical Biology, Faculty of Medicine, Yüzüncü Yıl
University,
larly in the middle-aged and elderly population [1]. Brain
65000 Van, Turkey ischemia is defined as decreased blood flow to brain tis-
e-mail: h-ozkol@mynet.com sues that prevents adequate delivery of oxygen, glucose,
and others nutrients leading to metabolic changes and
Assoc. Prof. S. Karadas
possible cell death [2].
Department of Emergency Medicine, Faculty of Medicine, Yüzüncü
Yıl University, The brain is particularly vulnerable to oxidative stress
65000 Van, Turkey because of its high rate of oxidative metabolic activity
e-mail: sevdegulkaradas@yahoo.com and intense production of reactive oxygen species (ROS)

13 Serum antioxidant enzymes activities and oxidative stress levels in patients with acute ischemic stroke   1
 original article
[3]. The higher ROS levels appear to play an important
role in the pathogenesis of ischemic [4] and hemor-
rhagic [5] brain injury [6]. Accumulating evidence has
suggested that significant increases in lipoperoxida-
tion products like malondialdehyde (MDA) have been
reported in stroke patients [7]. Several studies have
reported increased MDA levels in patients with ischemic
stroke [8–15].
The antioxidant enzyme, superoxide dismutase
(SOD), catalyzes the dismutation of O-2 to H2O2, thereby
preventing the accumulation of this free radical. H2O2
can be converted into H2O and O2 by catalase and/or
glutathione peroxidase (GSH-Px) [16]. The efficiency of
intracellular GSH-Px may be attributable to the facts that
it is located both in the cytosol and in the mitochondrial
matrix, can utilize lipid peroxides as well as H2O2 for sub-
strates, and has much higher affinity for H2O2 than cata-
lase [17]. A sensitive balance between the oxidative and
antioxidative mechanisms, such as GSH-Px, SOD and
catalase, help to protect vital cell components against
the neurological damage caused by the oxidative stress
related to brain ischemia [18].
Previous studies have assessed the role of antioxidant
enzymes activities in patients with acute ischemic stroke
[10, 12–15, 19–23] but these studies are conflicting. While
some authors reported lowered antioxidant enzymes
activities in patients with acute ischemic stroke [12, 14,
19–22], several studies have reported increased antioxi-
dant enzymes activities [13, 15, 23]. However, others have
reported no significance in antioxidant enzymes activi-
ties [10].
In the current study, we aimed to investigate how
oxidative and antioxidative parameters have changed
in patients with acute ischemic stroke within 24  h (the
onset of ischemia time), the days of 5th (the increase of
brain edema time) and 21st (damage recovery time) and
to figure out the relationship between these results and
the clinical status of patients.
Materials and methods
Subjects
This prospective case-control study was conducted in the
Department of Neurology at Yuzuncu Yıl University Med-
icine Faculty between June 2012 and September 2013.
The study group included 45 patients with acute cerebral
ischemic infarction.
Neither patients nor controls had a previous history of
a cerebrovascular event, cerebral hemorrhage, hemor-
rhagic infarct, or transient ischemic attack. Patients with
renal failure, hepatic or biliary disease, recent infection
or any immune disease, cancer, receiving any medicines
in the previous 2 months which could influence antioxi-
dant status (i.e., vitamins A, C, or E, Fe-containing com-
pounds, immunosupressive agents, xanthine oxidase
inhibitors or fibrates), alcoholism, smoking and other
nervous system diseases (alzheimer’s disease, parkin-
2   Serum antioxidant enzymes activities and oxidative stress levels in patients with acute ischemic stroke
son’s disease, amyotrophic lateral sclerosis, multiple
sclerosis) or psychiatric illness were excluded.
Each patient had a complete physical and neurologi-
cal examination, together with complete blood count,
blood chemistry, sedimentation rate and coagulation
tests, electrocardiography, pulmonary X-rays, and brain
diffusion-weighted magnetic resonance imaging. Also,
we applied Trial of Org 10172 in Acute Stroke Treatment
(TOAST) and Bamford classifications for the stroke sub-
type and etiology.
The severity of the neurological deficit was rated by the
National Institute of Health Stroke Scale (NIHSS) at the
time of admission and repeated on ischemic stroke days
5 and 21. Moreover, patients were evaluated according to
the modified Rankin Scale (MRS) after 3 months to deter-
mine the effects of the parameters studied on functional
outcome.
All blood samples were taken before any medication
including tissue plasminogen activator, anticoagulant,
antiaggregant, or anti-inflammatory drugs that might
influence the studied variables.
The blood samples were drawn from the patients
within the first 24  h post-stroke at the time of admis-
sion, on the days 5, 21, and 1 time in controls and serum
MDA levels, GSH-Px, SOD and catalase activities were
measured. These parameters were analyzed not only to
understand any difference between patients with stroke
and controls but also to figure out any changes at the
levels of these parameters taken mentioned times in the
patients.
A control group, matched for age and gender, was
composed of 30 healthy subjects who visited the hospital
for health examination during the same period of time.
The control subjects were asymptomatic with an unre-
markable medical history and with a normal physical
examination. None of the control subjects was receiving
anti-oxidant vitamin supplementation, such as vitamins
E and C. In addition, the control subjects were not receiv-
ing any drugs and were not smoking or consuming alco-
hol. Furthermore, the control subjects had no known
acute or chronic diseases.
The study protocol was conducted in accordance
with the Helsinki Declaration as revised in 2000 and was
approved by the local ethics committee. All of the sub-
jects were informed about the study and provided writ-
ten consent.
Blood sampling
Blood samples were collected to assess catalase, SOD,
GSH-Px activities, as well as MDA levels. Samples of
venous blood (2  ml) were taken from each participant
and placed into tubes with ethylenediaminetetraacetic
acid. The samples were stored in a cool box, at + 4 °C,
until they were transferred to the laboratory of the Medi-
cal Biology Department. The biochemical analyses were
done under the same conditions after the preparation of
all blood samples. Whole blood samples obtained from
13

each subject were hemolyzed with deionized water. After
centrifugation (4000 × g for 10  min at + 4 °C), the upper
supernatant fluid was separated, and oxidative stress
biomarkers (catalase, GSH-Px, SOD and MDA) were
measured at this stage.
Measurement of serum catalase activity
Catalase activity was measured using hydrogen peroxide
(H2O2) as substrate [24]. The disappearance of H2O2 was
followed at 240 nm, and enzyme activity was expressed
as k/g Hb at 25 °C.
Measurement of serum malondialdehyde levels
To determine the amount of lipid peroxidation in the
serum, the serum MDA levels were analyzed spectropho-
tometrically using the modified thiobarbituric acid-reac-
tive substance method reported by Placer and colleagues
[25]. The results were expressed as µmol/L.
Measurement of serum glutathione peroxidase
activity
The serum GSH-Px activity levels were measured spec-
trophotometrically at 412  nm, according to Lawrence
and Burk [26] and Matkovics and colleagues [27]. The
results were expressed as U/ml.
Measurement of superoxide dismutase activity
Serum SOD activity was assessed by determining the
inhibition percentage of formazan formation at 505 nm
in whole blood using commercially available kits (Ran-
dox-Ransod) on a spectrophotometer (Genesys 10S UV/
VIS Spectrophotometer, USA). The rate of inhibition of
the superoxide reaction by SOD was calculated accord-
ing to the definition of McCord and Fridovich [28]. The
results were expressed as U/ml.
Statistical analysis
The statistical analysis was performed using the Statisti-
cal Package for the Social Sciences (SPSS)13.0 (SPSS Inc.,
Chicago, IL, USA). Parametric values were expressed as
mean ± standard deviation. One-way ANOVA test was
applied to study the relationship between different vari-
ables. Comparisons of numeric values of all variables
were performed using the Mann-Whitney U-test or Stu-
dent’s t-test. Chi-square tests were used for analyzing
categorical variables. P value ≤ 0.05 was considered sta-
tistically significant.
13 Serum antioxidant enzymes activities and oxidative stress levels in patients with acute ischemic stroke   3
original article
Results
Of the 45 acute ischemic stroke patients, 15 (33.3 %) were
females, and 30 (66.7 %) were males. Of the 30 control
subjects, 10 (33.3 %) were females and 20 (66.7 %) were
males. The mean age of the patients was 64 ± 15 years,
and the mean age of the control subjects was 62 ± 8
years. There were no statistically significant differences
between the acute ischemic stroke patients and con-
trols with respect to gender and age (p > 0.05). According
to the Bamford classification, 36 of the stroke patients
had non-lacunar infarcts (partial anterior and posterior
sydromes) and 9 patients had lacunar infarcts. According
to the TOAST stroke subtype classification, 18 patients
had large-artery atherosclerosis, 11 had cardioembolism,
9 had small-vessel occlusion, 3 had stroke of other deter-
mined etiology (Factor 5 leiden mutation and secondary
to vasculitis), and 4 patients had stroke of undetermined
etiology. The scores of NIHSS in 1st, 5th, and 21st day were
10.86 ± 6.93; 7.78 ± 7.25 and 4.52 ± 6.48; respectively. At
the end of the third month, mean MRS score was calcu-
lated as 1.90 ± 1.44.
On the admission, serum MDA levels were higher
in acute ischemic stroke patients according to the con-
trols (p < 0.05), while serum catalase levels were lower
(p < 0.05). However, there were no significant differences
in the other parameters (GSH-Px and SOD activities).
On 5th day, results indicated that serum catalase and
SOD activities were significantly lower (both, p < 0.05),
whereas GSH-Px activity and MDA levels were not dif-
ferent (p > 0.05). Lastly, on 21st day, serum SOD activity
was significantly lower (p < 0.05) but MDA, GSH-Px lev-
els and catalase activities were not significantly different
(p > 0.05) (Table 1).
When the parameters were compared based on the
days, only serum SOD activity was significantly lower
in both 5th and 21st day than 1st day (p < 0.01, p < 0.001;
respectively) (Table 2).
There was no significant correlation among serum
antioxidant enzymes activities and oxidative stress levels
and Bamford, TOAST, NIHSS, and MRS scores (p > 0.05).
Discussion
In this study, we measured the activities of catalase, SOD,
and GSH-Px enzymes that are particularly important in
antioxidative defense in patients with ischemic stroke
within 1st, 5th, and 21st day after stroke onset. In addition,
we investigated the relationship between these results
and the clinical status of patients.
Stroke is a common and devastating event, which
often results in death or major loss of independence with
immense human and financial costs. The majority of
strokes are not fatal, and the major burden is long-term
disability. It is therefore the most important single cause
of severe disability among Western people living in their
own homes [29]. Risk factors for ischemic strokes are mul-
tiple and associated with a combination of multiple risk
 original article
Table 1  Serum antioxidant enzymes activities and oxidative stress levels in patients with acute ischemic stroke and controls
subjects
Parameters Controls
Catalase (k/g Hb) 247.42 ± 59.74
MDA (µmol/L) 5.90 ± 1.62
SOD (U/ml) 196.48 ± 4.65
GSH-Px (U/ml) 7.55 ± 2.06
Values are mean ± SD;
MDA Malondialdehyde, SOD Superoxide dismutase, GSH-Px Glutathione peroxidase
a
P < 0.05 compared with controls
b
P < 0.05 compared with controls
c
P < 0.05 compared with controls
d
P < 0.05 compared with controls
e
P < 0.05 compared with controls
Table 2  Comparison of serum antioxidant enzymes activities and oxidative stress levels in patients with acute ischemic stroke
according to days
Parameters 1st day
Catalase (k/g Hb) 220.39 ± 42.02
MDA (µmol/L) 6.77 ± 1.44
SOD (U/ml) 179.54 ± 31.22
GSH-Px (U/ml) 6.94 ± 1.21
Values are mean ± SD;
MDA Malondialdehyde, SOD Superoxide dismutase, GSH-Px Glutathione peroxidase
a
P < 0.01 compared with 1st day
b
P < 0.001 compared with 1st day
factors including hypertension, diabetes, cigarette smok-
ing, hyperlipidemia, atrial fibrillation, and obesity [30].
Since oxidative stress is an important mechanism
involved in ischemic stroke, the activity of antioxidant
enzymes may be an essential factor providing protec-
tion from neurological damage [13, 20, 31]. Increasing
evidence implicate oxidative stress in the pathogenesis
of ischemic brain injury [32, 33]. Oxidative stress, caused
by an imbalance between oxidant generation and anti-
oxidant defenses, plays an important role in brain aging,
neurodegenerative diseases, and other related adverse
conditions such as ischemia [34].
Circulating scavenging antioxidants with a high-redox
potential, such as reduced glutathione, as well as intra-
cellular antioxidant enzymes, such as GSH-Px, SOD, and
catalase, maintain this equilibrium [18]. The antioxidant
activity of plasma and erythrocytes may be an important
factor providing protection against neurological damage
caused by stroke-associated oxidative stress [35].
Several studies have investigated MDA levels in
patients with ischemic stroke [8–15, 36]. Sharpe et al. [36]
investigated MDA levels in patients with ischemic stroke.
They showed that MDA levels were significantly higher
in patients with ischemic stroke compared to those of
controls. In addition, Imre et al. [37] reported increased
erythrocyte MDA levels in patients with stroke. Aygul and
colleagues [12] reported increased plasma MDA levels
in patients with acute ischemic stroke. Similarly, Cojo-
caru et al. [14] reported increased plasma MDA levels in
patients with stroke. Ozkul et al. [15] reported increased
4   Serum antioxidant enzymes activities and oxidative stress levels in patients with acute ischemic stroke
Ist day 5th day 21st day
220.39 ± 42.02 a
210.90 ± 55.28b
225.44 ± 51.34
6.77 ± 1.44c 6.36 ± 1.25 6.64 ± 1.69
179.54 ± 31.22 172.82 ± 32.84d 169.83 ± 28.42e
6.94 ± 1.21 6.92 ± 1.31 7.06 ± 1.34
5th day 21st day
210.90 ± 55.28 225.44 ± 51.34
6.36 ± 1.25 6.64 ± 1.69
172.82 ± 32.84a 169.83 ± 28.42b
6.92 ± 1.31 7.06 ± 1.34
serum MDA levels in patients with acute stroke and sug-
gested deleterious effects of oxidative stress on clini-
cal outcome in acute ischemic stroke. Ferretti et al. [38]
found the higher level of lipid hydroperoxides in plasma
from stroke patients compared with control group. Con-
versely, Zimmermann et al. [13] found no significance
in plasma MDA levels in patients with acute ischemic
stroke. In the present study, we measured MDA levels
as a marker of oxidative stress and observed that serum
MDA levels were significantly increased in acute isch-
emic stroke compared with levels in healthy subjects.
Reports about the effects of SOD enzyme activity on
acute ischemic stroke are controversial. Cherubini et al.
[20] and Demirkaya et al. [21] found significantly reduced
SOD activity in acute ischemic stroke. In contrast, El
Kossi and Zakhary [10] did not find a significant differ-
ence in serum SOD activity between acute stroke patients
and controls. These contradictory results may be caused
by the existence of different SOD isoforms and varia-
tions in the methods used to measure SOD activity. We
observed significant decline in the serum SOD activity in
patients with acute ischemic stroke compared with levels
in healthy subjects when parameters were analyzed on
days 5 and 21.
GSH-Px enzyme is one of the most important and
powerful scavengers of free radicals in humans [27].
Demirkaya et al. [21] investigated erythrocyte GSH-Px
activity in acute ischemic stroke. They showed that eryth-
rocyte GSH-Px activity was significantly lower within 24 h
after the onset of stroke symptoms compared with con-
13

trol subjects. Several animal studies have revealed that
GSH-Px has protective effects for ischaemic brain injury
and that reduced GSH-Px levels are associated with
an increased stroke risk [22]. Aygul et al. [12] reported
decreased plasma GSH-Px activity in patients with acute
ischemic stroke. Cherubini et al. [20] found reduced
erythrocyte GSH-Px activity in patients with acute isch-
emic stroke. However, in our study, we found no signifi-
cance in serum GSH-Px activity in patients with acute
ischemic stroke compared with levels in healthy subjects.
Catalase serves as an intracellular antioxidant enzyme,
and it is a member of the free radical and ROS scaveng-
ing system [39]. Several clinical studies have investigated
catalase activity in patients with acute ischemic stroke.
Cojocaru et al. [14] found significantly decreased plasma
catalase activity in patients with stroke compared with the
control group. In contrast, Sheikh et al. [40] did not find a
significant difference in serum catalase activity between
acute stroke patients and controls. In the present study,
we observed that serum catalase enzyme activity was sig-
nificantly lower in acute ischemic stroke patients within
24 h after stroke onset than that of controls.
There is limited information regarding serum antioxi-
dant enzymes activities and MDA levels in patients with
ischemic stroke [14, 16, 23]. Kocaturk et al. [23] reported
reduced red blood cells catalase activity on days 3 and 5
than in controls. In addition, they observed that the low-
est red blood cells catalase activity on day 5 and at the
time SOD activity showed the peak value. As the red blood
cells SOD activity declined on day 10 of stroke and the
red cell catalase activity showed an increase compared to
the control group. In our study, SOD activity was reduced
significantly in the patients with acute ischemic stroke
on days 5 and 21. Recently, Cojocaru et al. [14] reported
increased plasma MDA levels and GSH-Px activity, while
decreased catalase and SOD activities at 7 days after
stroke. In the present study, we observed that serum cat-
alase and SOD activities were significantly lower in acute
ischemic stroke patients within 5 days after stroke onset
than controls. However, GSH-Px activity and MDA levels
were not significantly different. In addition, we found
that serum SOD activity was significantly lower in acute
ischemic stroke patients within 21 days after stroke onset
than controls. However, MDA levels, GSH-Px, and cata-
lase activities were not significantly different.
Measurements of oxidative stress could be useful to
understand stroke. MDA is a lipid peroxidation product,
and levels of MDA correlate with the size of ischemic stroke
and the clinical outcome [10, 41]. However, we observed
no statistically significant correlation among serum MDA
levels and Bamford, TOAST, NIHSS, and MRS scores.
Previous studies have reported the beneficial effects
of antioxidant supplementation in acute ischaemic
stroke [20, 36, 42]. Ullegaddi et al. [42] observed that
supplementary antioxidants immediately following
acute ischaemic stroke can enhance antioxidant capac-
ity and mitigate oxidative damage. Leinonen et al. [35]
reported an association between the plasma concentra-
tion of ascorbic acid and a-tocopherol and the degree of
13 Serum antioxidant enzymes activities and oxidative stress levels in patients with acute ischemic stroke   5
original article
neurological impairment after ischaemic stroke. Cheru-
bini et al. [20] found evidence of reduced plasma anti-
oxidant concentrations in ischaemic stroke patients and
that higher plasma vitamin A and uric acid concentra-
tions and lower plasma ascorbic acid concentrations and
erythrocyte SOD activity were associated with poor early
clinical outcome.
According to the results of this study, acute isch-
emic stroke patients have increased oxidative stress and
decreased antioxidant enzymes activities. Low antioxi-
dant enzymes activities may reflect the increased amount
of free oxygen radicals released in acute ischemic stroke.
We conclude that, at least in part, an imbalance of oxi-
dant and antioxidant status might play a role in the
pathogenesis of acute ischemic stroke. In addition, our
study shows that serum antioxidant enzymes activities
and oxidative stress levels of stroke patients decreases
gradually within 5 days compared to stroke onset. Fur-
ther studies are necessary to clarify this association.
Acknowledgments
The authors thank the staffs of Yuzuncu Yil University,
Medical Biology Department for their generous and
friendly assistance in every step of this study.
Conflict of interest 
The authors declared that there was no conflict of interest
and indicated that they did not have a financial relation-
ship with the organization that sponsored the research.
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