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(Stroke. 2000;31:3034.)
© 2000 American Heart Association, Inc.
Original Contributions |
Metalloproteinase Inhibition Reduces Thrombolytic (Tissue Plasminogen Activator)–Induced Hemorrhage After Thromboembolic Stroke
From the Department of Neuroscience, University of California at San Diego, La Jolla.
Correspondence to Dr Paul A. Lapchak, Department of Neuroscience, University of California at San Diego, MTF 316, 9500 Gilman Dr, La Jolla, CA 92093-0624. E-mail plapchak{at}ucsd.edu
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Abstract |
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Background and Purpose—A potentially dangerous side effect associated with tissue plasminogen activator (tPA) use is cerebral hemorrhage. We have focused on developing drugs that could be administered with tPA to reduce the rate of hemorrhage. Since recent studies suggest that various matrix metalloproteinases (MMPs) are important in tumor necrosis factor-
production and membrane and vessel
remodeling after ischemia, we investigated whether MMP
inhibition affected the rate of hemorrhage and infarct
production in the absence or presence of tPA
treatment. Methods—We occluded the middle cerebral artery of New Zealand White rabbits with radiolabeled blood clots. Five minutes after embolization, we administered either the MMP inhibitor BB-94 (30 mg/kg SC) or its vehicle. Additional groups received BB-94 or vehicle in combination with tPA, administered 60 minutes after embolization (3.3 mg/kg tPA). After 48 hours, the rabbits were killed and brains were removed, immersion fixed for 1 week in 4% paraformaldehyde, and then cut into 5-mm coronal sections that were examined for the presence of hemorrhage, infarcts, and recanalization.
Results—Hemorrhage after embolic stroke was detected in 24% of the control group. tPA induced macroscopically visible hemorrhage in 77% of the tPA-treated group. The rabbits treated with BB-94 had an 18% incidence of hemorrhage (P>0.05 compared with control). However, when the combination of BB-94 and tPA was administered to rabbits, there was only a 41% incidence of hemorrhage (compared with 77% in the tPA group; P<0.05). Both tPA and BB-94/tPA were similarly effective at lysing clots, at 49% and 35% (P<0.05), respectively, compared with the 5% rate of lysis in the control group. There was a trend for a reduction in the number of infarcts, but it did not reach statistical significance.
Conclusions—Our data suggest that MMP inhibition attenuates mechanisms involved in tPA-induced hemorrhage. This novel form of combination therapy may show promise as a treatment strategy for acute stroke.
Key Words: cytokines • intracerebral hemorrhage • ischemia • matrix metalloproteinases • membranes • neuroprotection • tumor necrosis factor
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Thrombolysis is now gaining increasing acceptance for acute stroke management; however, only a small subset of potentially eligible patients are being treated with tissue plasminogen activator (tPA).1 2 3 Overall, tPA is quite beneficial, even though there is a small window of opportunity for treatment and a potentially dangerous side effect of hemorrhages.2 4 5 6 A series of trials have shown that thrombolytics alone have limited efficacy,7 suggesting that additional treatment strategies are needed. Nevertheless, the finding that at least one acute therapy is effective in reducing neurological damage was an important proof of concept. Even though tPA is efficacious, there is one major shortcoming to the drug. tPA significantly increases the intracerebral hemorrhage (ICH) rate in patients approximately 10 times greater than that observed in placebo-treated controls, and half of the patients who develop symptomatic tPA-related ICH die.1 Because of this serious side effect, emphasis should be placed on continuing to develop new pharmaceuticals that can be used in combination with tPA2 8 to make tPA a safer stroke therapy.
Recently, a few research groups have focused on the role of
matrix metalloproteinases (MMPs) and non-MMPs in the processing of
tumor necrosis factor-
(TNF-)9 10 11
and in cerebral ischemia, edema, aneurysms, and
hemorrhage.12 13
When the multiple roles of MMPs in the central nervous system (CNS) are
considered, it is apparent that they may be involved in both membrane
remodeling and the production of cytokines that may be
deleterious to neuronal function and vasculature after a stroke.
Pharmacological intervention at the level of MMPs may minimize
stroke-induced tissue damage and reduce hemorrhage. Thus, we
studied whether pharmacological inhibition of MMPs, with the use of a
relatively nonspecific inhibitor, altered
hemorrhage rate or conferred neuroprotection in
embolized rabbits in the presence or absence of tPA
administration.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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The method we used has been described in detail.14 Male New Zealand White rabbits weighing 2 to 3 kg were anesthetized with halothane (5% in 3 L/min at induction, 3% in 3 L/min as a maintenance dose). The right internal carotid artery was exposed, and the external carotid artery and the common carotid artery were ligated. If any other branches were seen originating from the internal carotid artery, these were also ligated. A plastic catheter oriented toward the brain was inserted into the common carotid and secured with ligatures. The incision was closed around the catheter so that the distal end was accessible outside. The catheter was filled with 2 mL of heparinized saline (33 U/mL) and plugged with injection caps. The animals were allowed to recover from anesthesia for at least 2 hours before embolization.
Emboli were prepared by withdrawing 1 to 2 mL of arterial blood from a donor rabbit. The blood was mixed with a trace quantity of 57Co-labeled plastic microspheres (25 µm in diameter) and allowed to clot for 3 hours at room temperature. The clot was sliced with a razor blade into small cubes weighing approximately 3 to 4 mg. The cubes were suspended in phosphate-buffered saline containing 0.1% bovine serum albumin. The amount of radiolabel present in each cube was measured with a gamma counter. Just before the embolization, each animal was restrained, and the injection cap of the catheter was removed to allow the rabbit’s blood to fill the catheter and wash out the heparinized saline. The line was then filled with heparin-free normal saline. One of the clot cubes was placed inside the injection port of the catheter and rapidly injected with 3 mL of saline flush, followed immediately by a second 3-mL flush. Care was taken during both flushes to ensure that no air bubbles were present in the catheter or syringe. If the animal did not react behaviorally (nystagmus, hemiparesis, seizure) to the embolization, another blood clot was injected in the same way 3 minutes after the first embolization. If there was no behavioral reaction to either embolization, no further blood clots were administered. After the embolization process was completed, the catheter was ligated close to the neck, and the rest of the catheter and injection port were cut off.
Animals that died before they were killed were included in
this study; the brains were fixed and sectioned as below. The surviving
animals were killed 48 hours after embolization. The brains were
removed and immersion fixed in 4% paraformaldehyde for
at least 1 week and then examined by a blinded observer. The right
middle cerebral artery of each brain was examined for the presence of
emboli. The surface blood vessels were then stripped from the right
hemisphere of each brain and reserved. The cerebellum was also removed
from the brain and reserved. The remainder of the brain was cut into
six 5-mm-thick coronal slices, each having 2 faces. We noted the
presence, location, size, and type of each hemorrhage and
infarct. We recorded the size of hemorrhage as the number
of section faces showing
hemorrhage.15 16
Infarction was grossly visible as pale, softer tissue surrounded by
pink, normal brain tissue on the brain sections. Three major types of
hemorrhage were identified according to the grading system we
used in previous experiments. Hemorrhagic infarction (HI) was grossly
visible as red speckling of an area, usually surrounded by soft
infarcted tissue. Punctate hemorrhage (PH) was characterized by
isolated small red marks within the tissue that did not extend through
the tissue as a blood vessel would. Parenchymatous ICH was
characterized by a large homogeneous mass of blood within
the tissue. Examples of each type of hemorrhage are
represented in
Figure 1
. After evaluation for hemorrhage and
infarcts, the total radioactivity in the brains was measured by placing
the slices into a gamma counter. The surface vessels from the right
hemisphere were placed in a separate container. The cerebellum and each
hemisphere were then counted in separate tubes. The amount of
radiolabel present in the brain (including the right hemisphere
vessels) was compared with that contained in the labeled blood clot at
embolization. If <10% of the counts were found in the brain and
vessels, it was assumed that the labeled blood clot had not reached the
brain.16 17 The
data from these animals were excluded from further analysis.
Thrombolysis was defined in 2 ways, by recovery of
radioactive label and visual inspection. Any brains containing <20%
of the total recovered radioactivity in the surface vessels of the
right hemisphere were said to have undergone
thrombolysis of the embolus. Then, postmortem, we
recorded whether a clot was visible in the middle cerebral artery.
This observation correlated with the recovery of radioactivity in our
prior
study.14 18 19 20
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Drug Administration
We randomly allocated animals to 4 different
treatment groups before the embolization procedure. Sample size was
based on power analysis, with =0.05 and ß=0.90, a
coefficient of variation of 15%, and a difference between means of
20%. It was determined that a sample size of 12 to 14 animals per
group was required. However, our previous experience with this stroke
model indicates that we actually need an average of 20 animals,
including premature losses caused by various preparation difficulties
or deaths after embolization before treatment can be fully
administered. The treatments were as follows: tPA (n=60), BB-94 plus
tPA (n=26), vehicle (n=28), and BB-94 (n=17). In 2 groups of rabbits,
BB-94 or its vehicle was administered subcutaneously 5 minutes after
embolization. A fine suspension of BB-94 was freshly prepared in the
following vehicle: 0.9% normal saline containing 0.1% PF68 and 0.5%
carboxymethylcellulose. BB-94 was administered at a dose of 30 mg/kg on
the basis of the recommendation of Dr Helen Mills of British Biotech
(Oxford, UK). The recommendation was based on the pharmacokinetic
profile of BB-94 after peripheral injection. In the
remaining 2 groups of rabbits, we then administered tPA or vehicle 1
hour after embolization. The tPA regimen used in this study was as
follows: 3.3 mg/kg tPA, 20% as a bolus injection given over 1 minute,
followed by the remainder infused over 30
minutes.16 21
Genentech, Inc (South San Francisco, Calif) supplied tPA and its
vehicle. tPA was supplied as a lyophilized cake in 50-mg
configurations, containing 50 mg tPA (29 million IU), 1.7 mg
L-arginine, 0.5 g
phosphoric acid, and <4 mg polysorbate 80. The tPA was reconstituted
with sterile water for injection, at a concentration of 1 mg/mL. We
analyzed the data with the 
2 test
corrected for multiple comparisons, using the Bonferroni technique and
ANOVA when relevant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Stroke Success Rate
Of 131 embolized rabbits included in the study, we found that 84 rabbits (64%) had >10% recovered radioactivity in the brain postmortem. The behavioral manifestations of embolization included nystagmus, pupillary dilation, hemiparesis, or brief, uncoordinated jerking movements. There was a positive correlation between the appearance of abnormal behaviors after embolization, the presence of 57Co in brain resulting from the administered clot, and tissue damage. Even though we monitored the behavioral reaction to the embolus, the strict exclusion criteria were based on the presence of label in brain. The remaining 36% of the rabbits had
10% of the label present in the brain postmortem,
indicating that the injected blood clot did not reach the brain. The
breakdown of the 47 rabbits excluded from the study is as follows:
vehicle (n=7 of 28; 25%), tPA (n=25 of 60; 41%), BB-94 (n=6 of 17;
35%), and tPA/BB-94 (n=9 of 26; 35%). The rabbits that did not reach
the criteria were excluded from the study, and the data were not used
in the final analysis. This success rate corresponds well with
other studies involving this
model.17 18
Types of Hemorrhage After
Thromboembolic Stroke
Figure 1
shows 4 coronal brain sections from rabbits after
thromboembolic strokes. The top left panel shows an HI in the section
at the level of the septum and caudate putamen. The top right panel
shows an ICH and an HI in the putamen, globus pallidus, and thalamus.
The bottom left panel shows an ICH in the thalamus, and the bottom
right panel shows a PH in the hippocampus.
Hemorhage Rate
Figure 2 shows the hemorrhage rate for the 4 groups
of rabbits included in this study. The percentages of rabbits with
brain hemorrhages in the 4 groups were as follows: 24% in the
tPA/vehicle-treated group (n=21), 77% in the tPA-treated group (n=35),
18% in the BB-94–treated rabbits (n=11), and 41% in those treated
with the combination of BB-94 and tPA (n=17). Overall, there was a
statistically significant difference in hemorrhage rates
(Table).
tPA caused significantly more hemorrhages than in the
tPA/vehicle control group
(P<0.01). There was also a
significant difference in hemorrhage rate between the BB-94/tPA
and tPA groups (P<0.05). The
drug combination significantly attenuated the rate of
hemorrhage production. The hemorrhage rate
after a single bolus dose of BB-94 was also statistically different
from that of the tPA-treated group
(P<0.05).
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Hemorrhage Volume
The number of faces showing hemorrhage, a
qualitative measure of hemorrhage volume, is illustrated in
Figure 3. Because 5 brain slices were cut for each rabbit,
the maximum number of faces observed was 10. There were no
statistically significant differences among the 4 treatment groups. Of
the tPA-treated rabbits, there were 3.1±0.4 and 4.3±1.1 faces per
hemorrhage for the tPA-treated group and BB-94/tPA–treated
groups, respectively. In the tPA-control group, there was an average of
2.2±0.7 faces involved in each hemorrhage, whereas in the
BB-94–treated group, there was an average of 3.5±1.5 faces per
hemorrhage. By ANOVA, there was no statistical difference
between the hemorrhage sizes in any of the treatment or control
groups (P>0.05). A more
detailed analysis of hemorrhage volume using more
accurate quantitative methods is required.
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Types of Hemorrhage
The
Table
shows the types of hemorrhage present in each of the
experimental groups. Most of the hemorrhages seen were HI, but
ICH and PH were also present in each of the groups. Some of the
animals had >1 type of hemorrhage present in the brain.
For quantitative purposes, we treated each individual
hemorrhage observed as a separate entity. Hemorrhages
occurred throughout the brain and included the following structures:
caudate putamen; thalamus; hippocampus; frontal, parietal, and
occipital cortex; hypothalamus; suprachiasmatic area; cerebellum; pons;
and midbrain. There were no apparent differences among the groups in
the distribution of types or locations of hemorrhages. In the
tPA-treated group, BB-94 decreased the number of HI, PH, and
ICH.
Thrombolysis Rate
The main purpose of this series of experiments was to
determine the efficiency or efficacy of tPA when a second
pharmacological agent was administered. The results are shown in
Figure 4. We estimated thrombolytic efficacy
by calculating the percentage of animals in each treatment group that
had <20% of the total recovered radiolabel in the surface vessels of
the right hemisphere of the brain at
postmortem.18
Thrombolysis was found in 49% of the tPA-treated rabbits
(Figure 4), 5% of the tPA/control- treated rabbits, and 35%
of the combination drug–treated rabbits. There was no measurable
thrombolysis in the BB-94–treated group. There was no
significant difference in thrombolysis rate between the
tPA and BB-94/tPA groups. However, there were significant differences
when comparisons were made between either the tPA or BB-94/tPA groups
and the tPA-vehicle control group. There were also significant
differences when comparisons were made between either the tPA or
BB-94/tPA groups and the BB-94 control group.
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Infarct Rate and Volume
In a subset of 2 of the experimental groups used in
this study (tPA and BB-94/tPA groups), we determined whether MMP
inhibition affected infarct rate and volume (the number of brain slice
faces with infarcts) observed in brain after a stroke. In the tPA
group, infarcts were found in 94% of treated rabbits (15/16). In the
BB-94/tPA group, 65% of the rabbits (11/17) had infarcts. Although
there was a trend for BB-94–induced attenuation of infarct rate, the
values were not significantly different
(P>0.05). In the tPA-treated
group there was an average of 3.2±0.6 faces involved in each infarct,
whereas in the BB-94/tPA group there was an average of 5.1±0.8 faces
per infarct. There was no statistical difference between infarct
volumes measured in the 2 groups
(P=0.073). A more detailed
quantitative assessment of infarct volumes would conclusively determine
whether BB-94 affects infarct volumes.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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In the present study we found that the MMP inhibitor BB-94 effectively attenuated the rate of tPA-induced hemorrhage. However, BB-94 did not significantly alter the hemorrhage rate in the absence of tPA administration. In our model the most common type of hemorrhage observed is HI, the remainder being ICH and PH. HI is the most predominant type of hemorrhage in stroke patients, with primary ICH (8% to 15%) constituting most of the remainder.22 23 24 Thus, the thromboembolic model allows for representation of the types of hemorrhage observed in humans.
The observation that BB-94 inhibited the tPA-induced hemorrhage rate, but not the hemorrhage rate observed in controls, may be due to the low incidence of hemorrhage after a thromboembolic stroke in the absence of tPA. In only approximately 25% of the embolized rabbits do we observe hemorrhage. Thus, a treatment group in the range of 15 to 20 rabbits is too small to confidently conclude that BB-94 alone affected hemorrhage rate. However, since BB-94 reduced tPA-induced hemorrhage, our results suggest that BB-94 effectively inhibits CNS MMP activity after subcutaneous injection. However, BB-94 did not appear to affect hemorrhage volumes measured by the qualitative slice method described in this study. It is possible that a more accurate assessment of hemorrhage volumes could be determined by quantitative methods. Because the thrombolysis rate was not significantly different between the tPA-treated and BB-94/tPA–treated groups, it appears that the reduction of hemorrhage rate was not associated with inhibition of tPA activity in vivo. Our results showing that BB-94 reduced the hemorrhage rate are consistent with previous studies which suggested that MMPs may be important in blood-brain barrier and vasculature function and extracellular matrix remodeling after a stroke.25 26 For example, Romanic et al27 used a permanent middle cerebral artery occlusion model in the rat to show that MMP-2 and MMP-9 were increased in neutrophils, endothelial cells, and macrophages soon after stroke. They also showed that systemic administration of neutralizing antibodies to MMP-9 appeared to reduce brain injury after middle cerebral artery occlusion, suggesting that this MMP-9 is involved in neuronal damage after a stroke.27 The observation that MMP-9 is increased in endothelial cells suggests that MMP-9 may be involved in vasculature remodeling and weakening. Investigation of the gelatinases MMP-2 and MMP-9 in a nonhuman primate middle cerebral artery occlusion/reperfusion model showed that MMP-2 was significantly increased soon after stroke, whereas MMP-9 was only increased in subjects with hemorrhagic transformation.28 Bruno et al29 found a correlation between MMP-1 and MMP-2 and matrix remodeling. Overall, the studies suggest that at least 2 MMPs may be directly involved in the progression of stroke and hemorrhage, specifically MMP-2 and MMP-9. Pharmacological inhibition of MMPs with a nonspecific inhibitor has also previously been shown to reduce edema in a rat collagenase model.30
Regarding infarct rate and volume, we observed that BB-94 administration before tPA produced a trend for a reduction in infarct rates, which suggests that MMPs may also be involved in the ischemic response after embolization. This is in agreement with the findings of Romanic et al.27 However, although the rate of infarcts was slightly reduced, that is, there were fewer sites where infarcts were observed, there was a trend for larger areas of ischemic damage in the presence of BB-94 compared with tPA treatment. The reasons for this apparently contradictory finding require additional study and a more detailed quantitative assessment of infarct volumes and studies aimed at understanding the exact roles of MMPs in tissue damage after stroke.
Additionally, MMPs have been shown to be involved in the
production of cytokines in the CNS. Gearing et
al9 first demonstrated that
the mature TNF- precursor protein could be cleaved to biologically
active TNF- by several MMP enzymes, including the
collagenase MMP-1, gelatinases MMP-2 and MMP-9, and
stromelysins MMP-3 and
MMP-7.31 32 MMP-2
and MMP-9 have previously been shown to be active in the processing of
pro-TNF- to
TNF-.9 10 11 33
The authors also showed that specific MMP inhibitors such
as BB-2284 could block the production of biologically active
TNF-.9 In addition to
TNF- being produced via an MMP, TNF- can also induce MMPs (ie,
MMP-9) in the
CNS.34 35 36
This perpetuates the production of MMPs, enzymes that may be
deleterious to CNS vessels and membranes. Our findings with the
nonspecific MMP inhibitor BB-94, which inhibits MMP-9,
suggest that TNF- production may mediate certain aspects of
damage after thromboembolic stroke. Additional studies with more
specific MMP inhibitors are required to delineate the role
of various MMPs in stroke and in tPA-induced cerebral
hemorrhage.
Overall, our study is the first to show that effective combination drug treatments can be developed as novel treatments for stroke. In the present study preadministration of the MMP inhibitor BB-94 significantly reduced the tPA-induced hemorrhage rate and attenuated the brain infarct number. Thus, in effect, the administration of BB-94 improved the safety of tPA by reducing a side effect of tPA.
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Acknowledgments |
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This study was supported by grants NS28121 and NS23814 and a VA merit review grant to Dr Zivin. We would like to thank Dr Dalia M. Araujo for critical comments on the manuscript and Sonia Nunez and Jennifer Mazziota for technical assistance. BB-94 was supplied by British Biotech (Oxford, UK), and tPA was supplied by Genentech Inc (South San Francisco, Calif).
Received May 9, 2000; revision received July 24, 2000; accepted August 28, 2000.
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Editorial Comment
Department of Neurology Washington University School of Medicine St Louis, Missouri
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Tissue plasminogen activator (tPA) is the only therapeutic agent approved by FDA for treating ischemic stroke. In the NINDS study, tPA treatment group had a 10-fold increase in symptomatic intracerebral hemorrhage.R1 The increased hemorrhage rate has substantially curtailed the application of tPA in treating patients with acute ischemic stroke. tPA has to be given in strict adherence to the treatment protocol based on the NINDS study to achieve the desirable benefit against the hemorrhagic risk. It has been estimated as few as 2% of all patients with ischemic stroke have received tPA in this country. Any measure that may reduce the incidence of intracerebral hemorrhage associated with tPA may broaden its clinical use. In the preceding article by Lapchak and associates, a matrix metalloproteinase (MMP) inhibitor, BB-94, was found to be effective in reducing the hemorrhage rate in a thromboembolic stroke model in rabbits. MMPs, having been shown to cause the disintegration of vasculature,R2 are expressed after cerebral ischemia.R3 Thus, inhibition of MMPs is an attractive therapeutic strategy to prevent intracerebral hemorrhage after tPA therapy. Results presented by Lapchak et al are encouraging and suggest that therapeutic attempts to reduce hemorrhage rate after tPA treatment should be further advanced in preclinical and then clinical studies. Results from the present study also raised a number of questions that deserve further investigation. The first is the failure of BB-94 to reduce the hemorrhage volumes. Because the method used by the group was a rather crude one, quantitative assessment of hemorrhage volumes are needed in future studies. Since BB-94 did not appear to reduce infarct volumes, the reduced hemorrhage rate could not be attributed to its potential neuroprotective effects. Factors other than MMPs, however, may also contribute to tPA-induced intracerebral hemorrhage. One plausible mechanism is reperfusion injury of the ischemic vascular bed. Free radical spin-trapping has been shown to reduce the risk of intracerebral hemorrhage in rat models of stroke.R4 Together, these findings raise the hope that therapeutic measures that prevent structural disintegration and/or reperfusion injury of the ischemic vascular bed may be developed to broaden the clinical use of tPA in ischemic stroke.
Received May 9, 2000; revision received July 24, 2000; accepted August 28, 2000.
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1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med.. 1995;333:1581–1587.
2. Mun-Bryce S, Rosenberg GA. Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab.. 1998;18:1163–1172.
3. Armao D, Kornfeld M, Estrada EY, Grossetete M, Rosenberg GA. Neutral proteases and disruption of the blood-brain barrier in rat. Brain Res.. 1997;767:259–264.[Medline] [Order article via Infotrieve]
4. Asahi M, Asahi K, Wang X, Lo EH. Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab.. 2000;20:452–457.[Medline] [Order article via Infotrieve]
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