(Stroke. 2000;31:33.)
© 2000 American Heart Association, Inc.
Original Contributions |
Low Plasma Antioxidant Activity Is Associated With High Lesion Volume and Neurological Impairment in Stroke
From the Departments of Clinical Chemistry (J.S.L.), Neurology and Rehabilitation (J.-P.A., M.J., G.M.), Neurosurgery (K.L.), and Diagnostic Radiology (P.D.), Tampere University Hospital; Research Unit of Alcohol Diseases, University of Helsinki (H.A.); and the Department of Mental Health and Alcohol Research (H.A.), National Public Health Institute, Helsinki, Finland.
Correspondence to Hannu Alho, MD, PhD, National Public Health Institute, Department of Mental Health and Alcohol Research, PO Box 719, 00101 Helsinki, Finland. E-mail hannu.alho{at}ktl.fi
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Abstract |
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Background and Purpose—Oxidative stress is probably involved in neuronal damage induced by ischemia-reperfusion. The purpose of this study was to assess the role of antioxidant activity in cerebral ischemic stroke.
Methods—Antioxidant activity of blood plasma and cerebrospinal fluid was assessed in 22 patients with cerebral hemisphere infarction that was verified and quantified by MRI.
Results—Low total peroxyl radical trapping potential of plasma,
but not of cerebrospinal fluid, was associated with high lesion volume
and high neurological impairment assessed by scores on NIH Stroke
Scale, Barthel Index, and Hand Motor Score tests. The plasma
concentrations of ascorbic acid, 
-tocopherol, and
protein thiols were also associated with the degree of neurological
impairment.
Conclusions—These data suggest that the antioxidant activity of plasma may be an important factor providing protection from neurological damage caused by stroke-associated oxidative stress.
Key Words: antioxidants • cerebral infarction • cerebral ischemia • reperfusion • stroke
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Cerebral ischemia causes irreversible and fatal damage to part of the affected neurons, and the reperfusion and readmission of oxygen that follow may also be detrimental.1 2 During ischemia, high amounts of free radicals are formed by several mechanisms.1 Increased free radical formation together with a reduced antioxidant defense causes oxidative stress that may play a pivotal role in the pathogenesis of stroke-associated neuronal injury.1 3 Currently, there is evidence from both animal and human studies demonstrating that the oxidative damage to membrane lipids and proteins is, indeed, increased during cerebral ischemia and reperfusion (IR).4 5 6 7 It is, however, difficult to determine which part of the damage is caused by hypoxia and which by reperfusion.
Antioxidant activity is known to reflect the altered redox balance of
affected fluids, tissues, or organs in several pathological
states.8 9 Therefore, antioxidant concentrations or
measures of their activity have been used to estimate the amount of
oxidative stress. Also, measures of the total antioxidant potential of
biological fluids have been developed, and they have proved to be
useful tools for estimating the antioxidant activity in clinical
settings.10 11 12 During ischemia, cellular
glutathione (GSH) is rapidly depleted, and this also impairs the
regeneration of other antioxidants from their oxidized forms. Both
blood plasma and cerebrospinal fluid (CSF) contain powerful
chain-breaking antioxidants, such as -tocopherol,
ascorbic acid, uric acid, and protein-bound thiols. The concentrations
and activities of these antioxidants may be important determinants of
the IR-induced cerebral injury. The total antioxidant potential of CSF
is substantially lower than that of plasma, and the major component of
the potential in CSF seems to be ascorbic acid,13 while in
plasma it is uric acid.11 12
It has been shown14 that the plasma and cerebral tissue
levels of some antioxidants are decreased during IR in animals,
supposedly as a sign of increased oxidative stress. It has also
recently been reported15 that patients with acute
ischemic cerebral stroke have a lower plasma level of
cholesterol-adjusted vitamin A, -tocopherol,
and carotenoids than healthy controls. High plasma concentrations of
antioxidants have been associated with a decreased risk of cerebral
stroke in some epidemiological cross-sectional studies,16
but the antioxidant intervention trials to reduce the risk for stroke
have not been all encouraging.17 18
Little is known about the role of antioxidant activity in the prevention of stroke-associated neuronal damage and impairment after cerebral stroke. By providing protection from oxidative damage during IR, antioxidants could, in principle, limit the size of the cerebral lesion; therefore, low antioxidant activity could contribute to poor functional recovery. We attempted to test this hypothesis by assessing the antioxidant activity of plasma and CSF in 22 cerebral right hemisphere ischemic stroke patients in whom a volumetric MRI analysis of the infarction area and neurological functional tests were also performed.
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Subjects and Methods |
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Subjects
Thirty-three consecutive patients with acute infarction of the right cerebral hemisphere were initially recruited at the neurological ward of Tampere University Hospital, Tampere, Finland. The infarction was first diagnosed from clinical symptoms and CT scan on admittance. The diagnosis was then confirmed through MRI with a 0.5-T unit (General Electric Vectra) within 2 weeks (at days 4 to 14) from the stroke onset. The inclusion criteria were as follows: age not >75 years, right-handedness, no previous central nervous system diseases, no significant loss of hearing or sight, no significant physical handicap due to previous limb injury or disease, no other than current infarction-related cerebral changes in CT scanning, admittance to the neurological ward by the end of the third day after the infarction, and a level of consciousness of 0 or 1 by the NIH Stroke Scale19 ("alert/not alert, but arousable by minor stimulation to obey, answer or respond"). Lumbar puncture for CSF antioxidant analysis could not be performed in 11 patients because of current treatment with heparin or warfarin (n=9), risk of cerebral herniation (n=1), or death (n=1): These subjects were excluded from further analysis. Thus, the final study group consisted of 22 patients (9 women, 13 men). All patients underwent a planned neurological rehabilitation program during their stay in the hospital.
The mean age of the included subjects was 63.1 years (median 64.5, SD 10.2, range 25 to 75 years). Three patients were current smokers. Nine patients had hypertonia, 7 had coronary heart disease, and 1 had type 2 diabetes mellitus. None of the patients admitted usage of any antioxidant supplements when asked by a physician.
All patients gave written informed consent, and the study was accepted by the Ethics Committee of the Tampere University Hospital.
Methods
The neurological evaluation included the NIH Stroke Scale
(NIHSS), the Hand Motor Score (HMS), and the Barthel Index (BI). Each
evaluation was conducted by the same neurologist (J.-P.A.). NIHSS is
widely used to evaluate the neurological impairment resulting from
stroke.19 The theoretical maximum score in NIHSS is 34; a
score of 0 represents a totally asymptomatic
patient. The NIHSS does not include evaluation of hand motor function;
it was, therefore, assessed with HMS20 by a series of
tests: testing extension of fingers, independent finger movements,
holding a pen, pushing a syringe, unscrewing a small nut, and rotating
a round item. A force transducer was used to measure the strength of
hand squeeze and pinch grip force. Hand motor performance was
scored using a scale from 0 (normal function) to 24 (total paresis). BI
is a widely used assessment of patients’ level of independence in
activities of daily living.21 BI assessment consists of
several items that measure feeding, bathing, grooming, dressing, bowel
and urine control, chair transfer, ambulation, and stair climbing. In
BI the maximum score of 100 represents total independence and
0 a complete lack of independence.
The volumetric analysis of infarction size was conducted with digital MRI images and a semiautomatic segmentation algorithm in 14 patients. The newly developed segmentation algorithm and the AnatomaticTM software used have been described in detail elsewhere.22 Lesion volume was manually estimated from MRI images in 7 patients because of insufficient quality of the images for semiautomatic analysis. In 1 patient the MRI data were not available, and thus the lesion volume could be determined in only 21 of the 22 patients.
Samples for antioxidant activity of blood plasma and CSF were taken at 2 points: The first sample was taken within the first 3 days after infarction (t1, mean 2.2 days), and the second sample was taken between the fourth and the twelfth day after infarction (t2, mean 7.3 days). The clinical examinations were performed at corresponding time points (±1 days) and at 3, 6, and 12 months after the stroke. Venous blood was obtained by antecubital venipuncture into EDTA-containing vacuum tubes after an overnight fast. Plasma was immediately separated by centrifugation at 2800g for 10 minutes at 4°C. One hundred microliters of fresh plasma was mixed with 5% metaphosphoric acid before being frozen at -70°C for measurement of ascorbic acid. For the other antioxidant measurements, plasma was frozen and stored at -70°C; the storage time did not exceed 6 months.
Plasma total peroxyl radical–trapping potential (TRAP) was measured by
a chemiluminescence-enhanced method, as has been
described.12 13 23 2,2'-Azobis [2-amidipropanone]
hydrochloride (Polysciences) generates peroxyl radicals at a constant
rate at +37°C by thermal decomposition, and these radicals can be
detected by a chemiluminescence reaction enhanced with luminol (Sigma
Chemical Co). When a plasma or CSF sample is added, this reaction is
inhibited for a time that is directly proportional to the total peroxyl
radical–trapping antioxidative potential of the sample. The extinction
time of the sample is compared with that of 1 mole of water-soluble
tocopherol analog Trolox C (6-hydroxy-2,5,7,
8-tetramethyl-chroman-2-carboxylic acid; Aldrich Chemical Co), a
substance capable of scavenging 2 moles of peroxyl radicals per 1 mole
of Trolox C. The TRAP is expressed as micromoles of peroxyl radicals
trapped by 1 liter of the sample (µmol/L). For plasma, the calculated
TRAP (TRAPCalc) is derived from the
concentrations of the individual antioxidants based on their
stoichiometric peroxyl radical–trapping factors as follows:
TRAPCalc=[uric
acid]*2.0+[-tocopherol]*2.0+[ascorbic
acid]*0.7+[-SH]*0.4.24 Provision is left for an
unidentified fraction of measured TRAP,
(TRAPUnid), which is the difference between the
measured plasma TRAP and TRAPCalc
(TRAPUnid=TRAP-TRAPCalc).
The concentrations of uric acid and ascorbic acid were measured by
high-performance liquid chromatography (HPLC)
with an electrochemical detector.25
-Tocopherol was measured by a modified HPLC
method,26 in which ultraviolet detection was replaced with
an electrochemical detector, set to oxidation potential of +1.0 V
(Bioanalytical Systems Inc). The CSF concentrations of
-tocopherol were below the detection limit of 1
µmol/L, and therefore the TRAPCalc and
TRAPUnid were not calculated for CSF. The protein
thiol groups were determined as described.27
Statistics
The normality of the continuous variables was tested by the
Shapiro-Wilk W test, after which comparisons between the
antioxidant activity values at time points t1 and t2 were performed
with the Student paired t test. An unpaired Student
t test was used to compare independent groups.
Log-transformed values of infarction volume were used in the
statistical analysis. Correlation analyses were
performed with the Pearson product-moment correlation matrix.
Multiple regression analysis was used to identify determinants
of the plasma and CSF TRAP. Computations were conducted with a
microcomputer running Statistica for Windows 5.0 software (Statsoft
Inc). All data in the text are given as mean±1 SD unless otherwise
specified. A value of P<0.05 was considered
significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Individual baseline data for all study subjects is presented in Table 1
. The
mean volume of the cerebral infarction was 10.2±11.8
cm3 (range 0.1 to 44.7, median 8.6). The mean
values for NIHSS, HMS, and BI at baseline according to lesion volume
are presented in Table 2. The
volume of infarction had a significant correlation with the initial
score in NIHSS (r=0.57, P=0.007) and nearly
significant correlations with the initial scores in HMS
(r=0.43, P=0.05) and BI (r=-0.41,
P=0.07).
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The antioxidant activities of plasma and CSF at time points t1 and t2
are presented in Table 3. The
mean values of these 2 assessments were used in further
analyses, because the only statistically significant difference
between t1 and t2 was observed in the plasma level of
-tocopherol, which decreased 6.4%. The measured
individual antioxidant concentrations were entered in multiple
regression models: the major determinant of plasma TRAP was uric acid
(ß=0.71, P<0.0001); -tocopherol (ß=0.19,
P=0.29), ascorbic acid (ß=0.08, P=0.61), and
thiols (ß=0.00, P=0.99) did not reach statistical
significance. For CSF TRAP the significant determinants were ascorbic
acid (ß=0.66, P<0.0001) and uric acid (ß=0.62,
P<0.0001; for thiols ß=0.07, P=0.29). Plasma
TRAP had a correlation with CSF TRAP (r=0.47,
P=0.03). There were no gender-specific differences in the
plasma antioxidant concentrations or in the plasma TRAP. Men had higher
CSF TRAP than women (P=0.004) due to the higher CSF ascorbic
acid and thiol concentrations (data not shown), but no other
differences between males and females were observed. None of the
antioxidant parameters were associated with the age of the
study subjects or with smoking status. Patients with coronary
heart disease had an increased plasma level of uric acid, but there
were no other significant associations between the plasma antioxidant
activity and the presence of hypertonia, diabetes mellitus (n=1), or
coronary heart disease.
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Plasma TRAP had an inverse correlation with the volume of the
infarction (Figure, top panel). Patients with a lower than mean level
of plasma TRAP (1190 µmol/L) had a higher lesion volume than
patients with a higher-than-mean level of plasma TRAP (15.3±14.1
versus 5.6±7.1 cm3, P=0.03). The
infarction volume did not correlate significantly with any of the
measured individual plasma antioxidant concentrations, but a
significant inverse correlation was observed with the unidentified
fraction of measured plasma TRAP, ie, TRAPUnid
(Figure, middle). Neither CSF TRAP (bottom) nor any of the CSF
antioxidant concentrations was associated with the infarction
volume.
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Plasma TRAP had a significant or a nearly significant inverse
correlation with the scores in NIHSS and HMS and a direct correlation
with BI score at all time points after the stroke (Table 4). This was largely due to similar
correlations of plasma ascorbic acid, thiols,
-tocopherol, and the unidentified antioxidants with
NIHSS, HMS, and BI (Table 4). In CSF, no consistent
significant correlations between the antioxidant activity and
neurological test scores were observed (data not shown). Patients with
a lower-than-mean level of plasma TRAP had significantly poorer scores
in NIHSS, HMS, and BI at almost all time points (Table 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study demonstrates that the total antioxidant activity of plasma is associated with the volume of ischemic cerebral infarction and the degree of neurological impairment that follows. This was shown by correlations between plasma TRAP and MRI-based lesion volume and scores in neurological tests. Subjects with low plasma TRAP had a high lesion volume and a poor performance in neurological tests. The antioxidant activity of CSF, except for the CSF level of ascorbic acid, was not associated with the lesion volume or neurological findings.
The present study group consisted of 22 patients with newly diagnosed infarction of the right hemisphere. A similar location of the infarction in all patients allowed analysis of the association between the lesion size and the degree of neurological disability. Computed infarction volumes have been previously shown to possess an important prognostic value in the formation of neurological deficits after stroke,28 which was also confirmed in this study by use of a new MRI-based technique. Our relatively small study group, however, included both very small and large infarctions, which increased the dispersion of measured variables.
TRAP is a useful estimate of the total antioxidant activity of a given biological fluid. Changes in plasma TRAP have been observed in various clinical situations, including aging, lung cancer, acute infection, immobilization, diabetes mellitus, and coronary heart disease.12 Several modifications of the assay have been published, and they all share the same principle of producing peroxyl radicals at a steady rate.11 12 Because uric acid is present in high concentrations compared with other antioxidants in plasma, derivation of TRAPCalc by use of stoichiometric radical-trapping factors seems to be useful for analysis of the activity of other antioxidants. Although the individual antioxidants measured in this study form the majority of plasma TRAP, significant antioxidant activity remains unidentified (TRAPUnid). Several candidates have been proposed to be responsible for TRAPUnid. These include bilirubin, protein-based groups other than thiols, ubiquinole-10, carotenoids, flavonoids, free amino acids, glucose, lipid hydroperoxides in the lipid peroxidation chain reaction itself, cholesterol, steroids, and melatonin.29 Interestingly, of the antioxidant components of plasma, only TRAPUnid had a correlation with the infarction volume in the present study. TRAPUnid has been the only reactive component in some of our prior studies as well.29 30 31 32
It has been previously reported15 that the
cholesterol-adjusted concentrations of carotenoids and
-tocopherol, but not the concentrations of selenium,
thiols, or protein carbonyls, are lower in patients with
ischemic stroke than in healthy controls. These data suggest
that either the antioxidants in question are consumed or oxidized
during the cerebral IR process or that their levels are lower already
before the stroke. In the current study setting, measurement of the
antioxidant activity prior to the stroke was not possible, and
unaffected control subjects were not recruited. The levels of plasma
and CSF antioxidants in the stroke patients of the present study
were, however, comparable to those seen in control subjects of previous
studies conducted in our laboratory with the same methods and
equipment.12 13 23 29 30 31 32 We were also unable to detect
major changes in the antioxidant activity of plasma or CSF between the
2 early time points after the stroke. Nevertheless, the results of this
study provide no information about the association between the
antioxidant activity and the risk of stroke. Neither do the results
prove that antioxidant activity is a determinant of severity of
stroke—it can be vice versa.
It is not fully known whether the free radicals during IR are formed in the vasculature, the neuronal parenchyma, or both. It has been shown that the endothelium is involved in the generation of free radicals during reoxygenation and that lipid peroxidation is increased in cerebral arterioles during cerebrovascular injury.33 Ischemia may, however, lead to increased hydroxyl radical formation also in the parenchyma of the brain.34 The relative importance of the mechanisms of free radical generation may vary between different areas of the lesion, which is not homogenous in nature with regard to the rate and completeness of both ischemia and reperfusion. It has been demonstrated that intravenous administration of an antioxidant entering the neuronal parenchyma is more effective in reducing infarction size than administration of an antioxidant acting on the endothelium of the cerebral microvasculature.35 In our early MRI assessment, both the necrotic core and the edematous penumbra were included in the lesion volume, and it would have been interesting to reanalyze the association between antioxidant activity and the volume of the unrecovered brain mass at the end of the follow-up. This was not possible, however, due to resource limitations. The significance of the CSF antioxidant activity also remains to be further evaluated, because it was not associated with the severity of the stroke.
The treatment of cerebral stroke is still quite unsatisfactory, and new ways to improve the recovery and prognosis are needed. The results of this study suggest that there may be an association between the antioxidant activity of plasma and severity of ischemic stroke. Clinical evidence of the efficacy of antioxidants in prevention of neuronal damage after stroke is, however, lacking.
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Acknowledgments |
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This study was financially supported by the Medical Research Fund of the Tampere University Hospital, the Finnish Diabetes Research Foundation, the Emil Aaltonen Foundation, the Finnish Cultural Foundation, the Jalmari and Rauha Ahokas Foundation, and the Finnish Medical Foundation. Mrs Marja-Leena Lampén is acknowledged for her excellent technical assistance.
Received May 6, 1999; revision received June 26, 1999; accepted September 9, 1999.
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[Abstract/Free Full Text]
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S. K. Schiemanck, M. W.M. Post, Th. D. Witkamp, L. J. Kappelle, and A. J.H. Prevo Relationship between Ischemic Lesion Volume and Functional Status in the 2nd Week after Middle Cerebral Artery Stroke Neurorehabil Neural Repair, June 1, 2005; 19(2): 133 - 138. [Abstract] [PDF]
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 M. D. Lindner, V. K. Gribkoff, N. A. Donlan, and T. A. Jones Long-Lasting Functional Disabilities in Middle-Aged Rats with Small Cerebral Infarcts J. Neurosci., November 26, 2003; 23(34): 10913 - 10922. [Abstract] [Full Text] [PDF]
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J. Kanellis and R. J. Johnson Editorial Comment--Elevated Uric Acid and Ischemic Stroke: Accumulating Evidence That It Is Injurious and Not Neuroprotective Stroke, August 1, 2003; 34(8): 1956 - 1957. [Full Text] [PDF]
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 M Uno, K T Kitazato, K Nishi, H Itabe, and S Nagahiro Raised plasma oxidised LDL in acute cerebral infarction J. Neurol. Neurosurg. Psychiatry, March 1, 2003; 74(3): 312 - 316. [Abstract] [Full Text] [PDF]
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 S.E. GARIBALLA, T.P. HUTCHIN, and A.J. SINCLAIR Antioxidant capacity after acute ischaemic stroke QJM, October 1, 2002; 95(10): 685 - 690. [Abstract] [Full Text] [PDF]
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W.S. WARING Uric acid: an important antioxidant in acute ischaemic stroke QJM, October 1, 2002; 95(10): 691 - 693. [Full Text] [PDF]
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A. Chamorro, V. Obach, A. Cervera, M. Revilla, R. Deulofeu, and J. H. Aponte Prognostic Significance of Uric Acid Serum Concentration in Patients With Acute Ischemic Stroke Stroke, April 1, 2002; 33(4): 1048 - 1052. [Abstract] [Full Text] [PDF]
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F. P. D'Armiento, A. Bianchi, F. de Nigris, D. M. Capuzzi, M. R. D'Armiento, G. Crimi, P. Abete, W. Palinski, M. Condorelli, C. Napoli, et al. Age-Related Effects on Atherogenesis and Scavenger Enzymes of Intracranial and Extracranial Arteries in Men Without Classic Risk Factors for Atherosclerosis Editorial Comment Stroke, November 1, 2001; 32(11): 2472 - 2480. [Abstract] [Full Text] [PDF]
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A. Cherubini, M. C. Polidori, M. Bregnocchi, S. Pezzuto, R. Cecchetti, T. Ingegni, A. di Iorio, U. Senin, and P. Mecocci Antioxidant Profile and Early Outcome in Stroke Patients Stroke, October 1, 2000; 31(10): 2295 - 2300. [Abstract] [Full Text] [PDF]
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M. A. Topcuoglu and S. Demirkaya Low Plasma Antioxidant Activity Is Associated With High Lesion Volume and Neurological Impairment in Stroke Stroke, September 1, 2000; 31 (9): 2266 - 2278. [Full Text] [PDF]
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M. M. H. El Kossi and M. M. Zakhary Oxidative Stress in the Context of Acute Cerebrovascular Stroke Stroke, August 1, 2000; 31(8): 1889 - 1892. [Abstract] [Full Text] [PDF]
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