(Stroke. 2001;32:199.)
© 2001 American Heart Association, Inc.
Original Contributions |
Inhibition of 
4 Integrin Protects Against Transient Focal Cerebral Ischemia in Normotensive and Hypertensive Rats
From Biogen Inc, Cambridge, Mass.
Correspondence to Jane Relton, PhD, Biogen, Inc, 14 Cambridge Center, Cambridge, MA 02142. E-mail Jane_Relton{at}Biogen.com
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Abstract |
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Background and Purpose—The present study was performed to determine the role of
4 (CD49d),
a member of the integrin family of adhesion molecules, in
ischemic brain pathology.
Methods—Male
spontaneously hypertensive rats (SHR) or Sprague-Dawley rats underwent
60-minute middle cerebral artery occlusion (MCAO) followed by 23-hour
reperfusion. Animals were injected intravenously with 2.5
mg/kg anti-rat 4 antibody (TA-2) or isotype control antibody
(anti-human LFA-3 IgG1, 1E6) 24 hours before
MCAO. Infarct volume was quantified by staining of fresh tissue with
tetrazolium chloride and myeloperoxidase activity measured in SHR
tissue homogenates 24 hours after MCAO. In SHR, mean
arterial blood pressure was recorded before and after
MCAO in animals treated with TA-2 and 1E6.
Fluorescence-activated cell sorting
analysis was performed on peripheral blood
leukocytes before and after MCAO.
Results—TA-2 treatment significantly reduced total infarct volume by 57.7% in normotensive rats (1E6, 84.2±11.5 mm3, n=17; TA-2, 35.7±5.9 mm3, n=16) and 35.5% in hypertensive rats (1E6, 146.6±15.5 mm3, n=15; TA-2, 94.4±25.8 mm3, n=11). In both strains, TA-2 treatment significantly reduced body weight loss and attenuated the hyperthermic response to MCAO. In SHR, treatment with TA-2 significantly reduced brain myeloperoxidase activity. Resting mean arterial blood pressure was unaffected by treatment. Leukocyte counts were elevated in TA-2–treated rats. Fluorescence-activated cell sorting analysis demonstrated the ability of TA-2 to bind to CD3+, CD4+, CD8+, and CD11b+ cells in both naive animals and after MCAO.
Conclusions—These data
demonstrate that inhibition of 4 integrin can protect the brain
against ischemic brain injury and implicate
endogenous 4 integrin in the pathogenesis of acute brain
injury. The mechanism by which 4 integrin inhibition offers
cerebroprotection is independent of blood pressure modulation and is
likely due to inhibition of leukocyte
function.
Key Words: cerebral ischemia • inflammation • integrins • leukocytes
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Infiltration of inflammatory cells is now established as a central component in the development of ischemic infarction in the brain.1 2 The temporal resolution of cellular infiltration has been characterized in various animal models of stroke,2 3 4 supporting the prevailing dogma that attributes brain inflammation to the detrimental actions of polymorphonuclear leukocytes (PMNs).5 These cells are reportedly the first to enter the brain after injury.3 The presence of monocytes, macrophages, and T cells in the brain after ischemia has also been documented,6 7 and manipulation of these immune-competent cell populations has been shown to protect the central nervous system (CNS) against ischemic injury.8 9
The trafficking of cells into the brain is dependent on the
expression of adhesion molecules and their counter receptors on
migrating cells and on the cerebrovascular
endothelium.10
Three families of adhesion receptors have been identified: selectins,
immunoglobulins, and
integrins.10 The integrins
are a group of heterodimeric glycoproteins consisting of
and ß subunits.11 The
integrin 4, first identified on T
cells,12 forms a heterodimer
with both ß1 and ß7 subunits. 4ß1/Very late antigen-4 (VLA-4,
CD49d/CD29) is constitutively expressed on all leukocyte subtypes and
binds to vascular cell adhesion molecule-1 (VCAM-1) on inflamed
endothelial cells, as well as macrophages and
dendritic cells.13 The
extracellular matrix protein osteopontin has also been identified as a
ligand for 4ß1.14
4ß7/Lymphocyte-Peyer’s patch adhesion molecule-1 (LPAM-1,
CD49d/CD103) is expressed on almost all leukocyte subtypes and binds to
mucosal addressin cell adhesion molecule-1 (MAdCAM-1), present in
the gut, and to VCAM-1.13
Both 4ß1 and 4ß7 also bind to an alternately spliced form of
the extracellular matrix protein
fibronectin.13 Functionally,
4ß7 is thought to be involved in lymphocyte homing to the gut,
whereas 4ß1 has been associated with lymphocyte recruitment in
immune cell–mediated disease
pathology.13 At the
blood-brain barrier, 4 integrin/VCAM-1 adhesion interactions have
been shown to play a crucial role in T cell migration into the
CNS.13 15 In
vitro VCAM-1 is markedly upregulated in response to inflammatory
stimuli on murine and human cerebrovascular endothelial
cells,16 17
neuronal cells,18 and
astrocytes.19 Expression of
mRNA for VCAM-1 occurs on the luminal surface of inflamed vessels and
on perivascular cells after focal cerebral ischemia in the
rat,6 and VCAM-1 protein is
intensely expressed in ischemic brain tissue taken from stroke
patients.20
It was generally accepted that PMNs do not express
4 integrin. However, recent studies have demonstrated the presence
of 4 on rat, mouse, and human
neutrophils21 at a level
sufficient to mediate binding to VCAM-1 and MAdCAM-1 under static or
low-flow conditions.22 Under
laminar flow conditions, few unstimulated PMNs bound to purified
VCAM-1, but PMNs from rats in a chronic inflammatory state adhered more
avidly.21 Inhibition of 4
integrin decreased PMN infiltration through connective tissue
fibroblast barriers23 and
reduced adhesion to endothelial cells or extracellular
matrix induced by chemotactic
stimuli.24 In animal models,
the functional role of 4 integrin–mediated leukocyte adhesion has
been demonstrated in several models of autoimmune/inflammatory
disease.21
The role of 4 integrin in the brain after acute
injury has not previously been investigated. The objective of this
study was to determine whether 4 integrin plays a functional role in
the pathogenesis of ischemic brain damage in vivo. To address
this question, we determined the effect of anti–4 integrin antibody
(TA-2)25 treatment on brain
damage in a rat model of transient focal cerebral ischemia.
Inhibition of 4 integrin significantly improved neurological outcome
in both normotensive and hypertensive rats. Because of the relevance of
hypertension to stroke pathology and in the interest of minimizing
animal numbers, separate experiments to elucidate potential mechanisms
of action of TA-2 were performed only on hypertensive rats. In
spontaneously hypertensive rats (SHR), myeloperoxidase (MPO) activity
was significantly reduced in the ischemic hemisphere of rats
treated with TA-2 compared with 1E6-treated controls. Cerebroprotection
was observed in the absence of alteration in blood pressure.
Fluorescence-activated cell sorting (FACS)
analysis of peripheral white blood cells (WBCs)
demonstrated the ability of TA-2 to bind to circulating leukocytes.
These data demonstrate that endogenous 4 integrin plays
a role in the generation of ischemic brain damage, probably via
inhibition of leukocyte function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Antibodies
In vivo studies used mouse anti-rat
-4 antibody
(TA-2; Seikagaku America Inc) and isotype control mouse anti-human
LFA-3 IgG1 (1E6; Biogen Inc). For FACS
analysis, fluorescein isothiocyanate
(FITC)–labeled mouse anti-rat antibodies anti-CD3, anti-CD4, anti-CD8,
and anti-CD11b were purchased from PharMingen, and phycoerythrin
(PE)-labeled goat anti-mouse Ig was purchased from Jackson Immuno
Research.
Middle Cerebral Artery Occlusion
All experiments were performed within the guidelines
of the institutional animal care and use committee. Animals had free
access to food and water and were on a 12-hour/12-hour light/dark
cycle. Body weight was recorded before surgery and again before the
animals were killed.
Male SHR (weight, 250 to 350 g; Taconic, Germantown, NY) or male Sprague-Dawley rats (weight, 270 to 300 g; Charles River, Wilmington, Mass) were injected intravenously with 2.5 mg/kg TA-2 (n=16 Sprague-Dawley rats, n=15 SHR) or 1E6 (n=17 Sprague-Dawley rats, n=11 SHR) 24 hours before induction of cerebral ischemia. Animals underwent 60 minutes of transient occlusion of the right middle cerebral artery (MCA) by the suture method, as described previously26 . Briefly, animals were anesthetized in 3% isoflurane (Fort Dodge Animal Health). A midline incision was made in the neck to expose the junction of the common and internal carotid arteries. Cerebral ischemia was induced by insertion of a poly-L-lysine coated 4-0 nylon monofilament (Ethicon Inc), with a rounded tip, up the internal carotid artery to the origin of the MCA. The incision was closed, and the animals were allowed to recover from anesthesia. One hour later the animals were reanesthetized, the incision was reopened, and the filament was retracted to allow reperfusion of the ischemic tissue. The incision was closed, and the animals were allowed to recover. Animals were tested for behavioral deficits at the time of reperfusion. Animals that did not exhibit marked behavioral deficits, namely, forelimb flexion and circling on bench indicative of hemiparesis, were excluded from the study. Body temperature was monitored with a rectal probe and recorded at the time of arterial occlusion and again at the time of reperfusion. Twenty-four hours after the induction of cerebral ischemia, animals were killed by CO2 inhalation. Brains were immediately removed and placed in 4°C saline for 10 minutes, then cut into 7x2-mm coronal slices in a rodent brain matrix (David Kopf Instruments); sections were stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC, Sigma). The area of infarction on each brain section was sketched onto stereotaxic maps and quantified by image analysis (Image-Pro 3.0). In a separate study the same experimental protocol was followed until the animals were killed, when animals were transcardially perfused with 50 mL 4°C saline. Brains were removed and cut coronally, giving a 4-mm block of tissue that was bisected into right and left hemisphere samples for measurement of MPO activity.
MPO Assay
MPO activity was measured with the use of a modified
version of the assay originally described by Barone et
al.27 Tissue samples were
weighed and homogenized (Fisher Scientific) in 2 mL 50
mmol/L Tris-HCl (pH 7.4) at 4°C. The homogenate was added
to 20 mL 5 mmol/L
K2HPO4 (pH 6.0) and
centrifuged at 30 000g
at 4°C for 30 minutes. Supernatant was removed, and the pellet was
washed and resuspended in 0.5% hexadecyltrimethylammonium
bromide (HTAB, Sigma) in 50 mmol/L
K2HPO4 (pH 6.0) at 1:5
original wet weight to volume ratio for 2 minutes at 25°C. Three
freeze/thaw cycles were then performed with sonications. Samples were
incubated for 20 minutes at 4°C, then centrifuged at
12 500g (15 minutes at 4°C).
Supernatant was collected and assayed for MPO activity. Then 74 µL
80 mmol/L K2HPO4,
(pH 5.4), 5 µL 10% HTAB, and 10 µL 16 mmol/L 3,3',5,5'
tetramethyl benzidine were added to wells of a flat-bottomed 96-well
plate at 4°C. Sample supernatant (50 µL) was added to assay
reagents, and the plate was incubated at 37°C for 5 minutes. The
reaction was initiated by addition of 50 µL 30 mmol/L
H2O2 to each well, and
the plate was incubated at 37°C for 15 minutes. Human leukocyte MPO
(Sigma) was used for standard concentrations. MPO activity was detected
photometrically on a plate reader at 620 nm (Molecular Devices,
Thermomax).
Blood Pressure Measurement
In a separate study, naive SHR were
anesthetized with thiobutabarbital (100 to 110 mg/kg IP;
Inactin, RBI), and the femoral artery was cannulated with polyethylene
tubing (PE50) to record resting blood pressure. Blood pressure was
recorded for 30 minutes, and mean arterial blood
pressure was taken as the average of the 30-minute recording.
The same procedure was performed on separate groups of animals 24 hours
after MCA occlusion (MCAO).
WBC Counts
Blood was drawn from SHR by cardiac puncture for
measurement of WBC counts after either no treatment or surgery, 24
hours after treatment, or 24 hours after MCAO. Blood was collected in
EDTA-coated tubes, and differential WBC counts were performed with an
Abbott Cell Dyn 350 apparatus.
FACS Analysis
Differential WBC counts of fresh
Li-heparin–anticoagulated whole blood from SHR were performed with an
Abbott Cell Dyn 3500 apparatus. Red blood cells were lysed
by hypo-osmotic shock. Remaining peripheral blood
lymphocytes were washed twice and incubated with TA-2 (10 µg/mL) for
20 minutes at room temperature. Cells were washed and incubated with
the secondary PE-labeled goat anti-mouse Ig (0.5 µg/mL) to localize
the TA-2. Cells were washed again and incubated with FITC-labeled mouse
anti-rat CD3, CD4, CD8, or CD11b or matched isotype (1 µg/mL). Cells
were washed twice with FACS buffer, fixed in 1%
paraformaldehyde, and analyzed on a FACScalibur
unit (Becton Dickinson). Staining was analyzed with the use of
the CellQuest software package (Becton Dickinson), plotting FITC
staining against PE staining.
Statistical comparisons between 2 groups were analyzed by unpaired Student’s t tests. Multiple comparisons were made with repeated-measures 1-way ANOVA with Student-Newman-Keuls post hoc test. All results are expressed as mean±SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Transient MCAO resulted in reproducible infarction of the right hemisphere of the brain detected by TTC staining 24 hours after induction of cerebral ischemia in SHR and Sprague-Dawley rats. Damage was sustained to both cortical and subcortical regions and was more extensive in SHR than in Sprague-Dawley rats. These observations are consistent with previous reports.28
In SHR, pretreatment with anti-rat 4 antibody TA-2
(2.5 mg/kg IV) 24 hours before induction of cerebral ischemia
significantly reduced total and subcortical mean infarct volume
compared with animals treated with the same dose of an isotype control
antibody, 1E6
(Figure 1
; total, 146.5±15.5 versus 94.4±25.85
mm3,
P<0.05; subcortical,
43.1±1.98 versus 30.47±4.57 mm3,
P<0.01). Cortical infarction
was reduced by a comparable extent, but this effect did not quite
attain statistical significance (103.45±14.3 versus 63.9±21.8
mm3,
P=0.053). The degree of brain
infarction in 1E6 antibody–treated animals was identical to that seen
previously in PBS-treated animals (data not shown). In Sprague-Dawley
rats, the same pattern of protection was observed in TA-2–treated rats
as in SHR
(Figure 1; total, 84.2±11.5 versus 35.7±5.9
mm3,
P<0.001; cortical, 37.3±9.0
versus 23.65±5.7 mm3,
P=0.1; subcortical, 36.6±3.7
versus 12.2±5.2 mm3,
P<0.001).
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Body weight was recorded before surgery and again
before the animals were killed. Treatment with TA-2 significantly
reduced weight loss over the experimental period compared with
1E6-treated animals in SHR and Sprague-Dawley rats
(Figure 2). In both strains body temperature was
elevated from preischemic levels when recorded at the
time of arterial reperfusion. TA-2 treatment significantly
attenuated this increase in body temperature
(Figure 2). In the absence of MCAO, TA-2 or 1E6 treatment had
no effect on body temperature (data not shown).
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PMN infiltration into ischemic tissue was
quantified by MPO assay. Tissue homogenates from SHR
treated with TA-2 had significantly reduced MPO activity compared with
that measured in tissue homogenates from 1E6-treated rats
(Figure 3).
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Mean arterial blood pressure was
comparable in 1E6- and TA-2–treated animals both before and after
MCAO. Mean arterial blood pressure in naive SHR was
comparable to that observed in the treatment groups
(Table 1).
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Total WBC counts were significantly elevated in
TA-2–treated animals compared with untreated animals and animals
treated with an isotype control antibody before and after MCAO
(Table 2). Lymphocyte numbers were primarily responsible for
the observed increase in circulating cell population in response to
TA-2. A reduction in total WBC count and circulating lymphocyte count
was observed in all groups that had undergone MCAO compared with
unoperated animals. No significant differences between groups were
observed in absolute PMN numbers; however, MCAO induced an increase in
percentage of PMNs in untreated and 1E6-treated animals that was not
observed in the TA-2–treated group
(Table 2).
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FITC-labeled cellular markers identifying CD3, CD4,
CD8, and CD11b domains on peripheral blood leukocytes
(PBLs), isolated from SHR before and after MCAO, were used to
differentiate T cells (CD3); MHC II T cells, monocytes, and
macrophages (CD4); MHC I T cells, T helper cells, and natural
killer cells (CD8); and neutrophils and myeloid cells (CD11b).
PBLs were double labeled with PE/TA-2, and FACS analysis
revealed TA-2 binding to all differentiated populations
(Figure 4). In the absence of labeled antibodies to either
cellular markers or TA-2, no fluorescence was observed. A
significant increase in CD11b+/TA-2+ populations and a significant
decrease in CD3+/TA-2+ and CD4+/TA-2+ populations were observed 24
hours after MCAO
(Figure 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Pretreatment with anti-rat
4 antibody (TA-2)
significantly reduced the extent of brain infarction compared with
isotype antibody–treated controls in both normotensive and
hypertensive animals measured 23 hours after 60-minute MCAO. The
protective effect of TA-2 was more pronounced in normotensive than in
hypertensive rats. This may be due to strain differences in 4
expression or infarct development or may suggest a more pronounced
effect of TA-2 after milder injury. The dose of antibody used in these
studies (2.5 mg/kg) provides coverage of 4 sites on PBLs for
approximately 72 hours after injection (D. Leone et al, unpublished
data, 1999) and has previously been shown to ameliorate symptoms
in numerous models of autoimmune disease, demonstrating its efficacy in
vivo.13 Similarly, the
isotype control antibody 1E6 has previously been used in animals
without immune or physiological
effect.13 A pretreatment
regimen was undertaken to ensure 4 coverage at the time of induction
of cerebral ischemia and thus unequivocally demonstrate a
functional role for 4 in the pathogenesis of acute brain damage. The
use of a 24-hour pretreatment paradigm, however, opens up the
possibility of a tolerance-inducing effect of the treatment
administered, which itself can confer protection from a subsequent
insult.29 30 It
is unlikely that this is the mechanism of action of TA-2 since studies
by Becker et al,31 described
in an article also published in this issue of
Stroke, demonstrated the
protective effect of TA-2 treatment when administered 2 hours after
MCAO. A febrile response is often observed in response to brain injury both under experimental conditions32 and in the clinic33 and was observed here in response to 60-minute MCAO. A correlation between the degree of hyperthermia and clinical outcome has been established,33 and it has been proposed that fever may act as a surrogate marker for brain inflammation.2 In this study TA-2 treatment significantly attenuated the hyperthermic response of animals to MCAO. It is well established that hypothermia protects the brain against ischemic infarction,34 and the present data may be interpreted to suggest that the protective effect of TA-2 was due to attenuation of ischemia-induced hyperthermia. It is also plausible that this effect is due to a reduced degree of inflammation, which has been correlated with the severity of brain damage.35 The latter hypothesis is supported by the observations of Becker et al,31 who report inhibition of brain infarction but no effect of TA-2 on body temperature when the antibody was administered 2 hours after MCAO.
Leukocyte counts differed markedly between treatment
groups, and elevated lymphocyte numbers were predominantly responsible
for increased total leukocyte count in TA-2–treated groups.
Peripheralization of hematopoietic cells in response to
anti-4 treatment has been reported
elsewhere.13 36
Elevated WBC count may be due to reduced lymphocyte adhesion and
mobilization of lymphocytes from lymph nodes and
spleen.36 Inhibition of
leukocyte adhesion may reduce brain damage by prevention of the
"no-reflow" phenomenon37
and postischemic
hypoperfusion,38 39
in which WBCs physically plug and obstruct microvessels. This can
result in the localized release of vasoactive mediators and direct
injury of endothelial cells. Inhibition of adhesion
also results in decreased cell trafficking into the injured CNS, as
demonstrated by the ability of TA-2 to reduce MPO activity in
ischemic tissue.
FACS analysis demonstrated 4 expression and
TA-2 binding to CD3+, CD4+, CD8+, and CD11b+ circulating blood cells
both before and after MCAO. These findings are in agreement with
previous reports describing 4 expression on T cells, monocytes,
macrophages, natural killer cells, and
PMNs.21 All of these cell
types have been implicated in ischemic brain
pathology,3 6 7 8 9
and inhibition of their actions can protect against the development of
infarction.5 8 9
The profound effect of TA-2 treatment on circulating lymphocyte numbers
indicates inhibition of T cell adhesion to the vascular
endothelium in all organs, including the brain. This
may inhibit the potentially detrimental effects of T cell trafficking
into the injured CNS, which in turn may protect against
ischemic brain damage, in addition to the potentially
beneficial effects of reduced PMN
infiltration.5 10
It is unclear from the present study whether the
heterodimeric unit responsible for mediating 4-dependent cell
trafficking after focal cerebral ischemia is 4ß1 (VLA-4)
or 4ß7. VCAM-1, which is upregulated in the cerebrovasculature in
response to stroke20 or
inflammatory
stimuli,16 17 is
the primary counter receptor for
VLA-4.13 Lymphocytes
infiltrating the CNS during chronic inflammation bind to VCAM-1 but not
MAdCAM-1, the primary counter receptor for
4ß7,16 and MAdCAM-1 is
reportedly not expressed on cerebrovascular endothelial
cells in response to inflammatory
stimuli.17 Osteopontin also
acts as a counter receptor for
VLA-4.14 Message for this
protein is upregulated as early as 6 hours after permanent MCAO in SHR,
but a role in glial scar formation, rather than the acute inflammatory
response, was proposed.40 An
alternately spliced form of the extracellular matrix protein
fibronectin (CS-1) can also act as a ligand for 4
integrins,13 and synthetic
CS-1 fibronectin peptides protected against ischemic injury
after reversible MCAO.41
Taken together, current evidence suggests that after cerebral
ischemia, 4-dependent events are primarily mediated by
VLA-4/VCAM-1 interactions. However, the promiscuous nature of integrin
family members and their counter receptors permits redundancy in the
system and does not allow one to attribute the actions of a ligand to a
particular counter receptor.
Over recent years, inhibition of adhesion molecules
has provided an attractive target for the development of novel
therapeutics for the treatment of stroke. Interventions have focused on
inhibition of PMN infiltration into the injured brain. Experimental
results have been
variable5 and clinical
trials
disappointing.42 43
Since 4 integrin is expressed on almost all leukocyte subtypes, the
present results extend the pathological importance of leukocytes
beyond the PMNs; consequently, inhibition of 4 integrin may offer
advantages over therapies that selectively target PMN adhesion and
transmigration after stroke.
In conclusion, the present data demonstrate a
functional role for 4 integrin in the pathological responses to
cerebral ischemia in normotensive and hypertensive rats. The
mechanism by which TA-2 provides cerebroprotection appears not to be
due to modulation of blood pressure. TA-2 bound to differentiated cell
populations that are thought to be involved in ischemia-induced
brain inflammation and injury caused a marked lymphocytosis and
significantly reduced PMN infiltration into ischemic tissue.
These findings support the hypothesis that TA-2 acts by inhibition of
adhesion and transmigration of leukocytes into the
brain.
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Acknowledgments |
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The authors would like to acknowledge Michael Huff and Sussie Castro for their technical assistance.
Received May 12, 2000; revision received July 12, 2000; accepted August 28, 2000.
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Editorial Comment
Departments of Neurosurgery and Neurology Stanford University School of Medicine Stanford, California
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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It is now well established that the inflammatory response during stroke contributes significantly to the worsening of acute ischemic injury. For leukocytes to gain access to their target tissues, a variety of signaling proteins and adhesion molecules act in concert to permit chemotaxis, endothelial cell attachment, and transmigration. Among the most studied of these molecules are the intercellular adhesion molecules (ICAM), the selectins, and the leukointegrin CD11/CD18. Several prior experimental stroke studies have repeatedly shown that inhibition of 1 or more of these molecules reduces infarct size and improves neurological outcome. As a result, 2 clinical stroke trials emerged, only to fail at the phase 3 level.R1 In their article, Relton et al show that antibody inhibition by TA-2 of a novel leukocyte target, the
4 integrin, not only reduces leukocyte
infiltration into ischemic brain but attenuates injury in 2
different rat strains. A detailed analysis of TA-2 is provided,
and the authors were careful to use an antibody-treated (1E6) control
group. They also showed that TA-2 blunted the postischemic
hyperthermic response. Given the potentially damaging effects of fever
during stroke, there may be additional benefits to this treatment as
well. However, the antibody was administered prior to ischemia
onset; posttreatment administration would be more clinically relevant.
Nevertheless, this paper suggests a novel new "antileukocyte"
approach to treatment of acute ischemic stroke. Received May 12, 2000; revision received July 12, 2000; accepted August 28, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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1. Sherman DG, for the Enlimomab Acute Stroke Trial Investigators. The Enlimomab Acute Stroke Trial: final results. Neurology. 1997;48:A270. Abstract.
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