From the Department of Cardiovascular Pharmacology, SmithKline Beecham
Pharmaceuticals, King of Prussia, Pa.
Correspondence to Dr Anne M. Romanic, Department of Cardiovascular Pharmacology, UW2510, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, King of Prussia, PA 19406. E-mail anne_romanic-1{at}sbphrd.com
Background and Purpose—Matrix
metalloproteinases (MMPs) are a family of proteolytic enzymes that
degrade the extracellular matrix and are implicated in numerous
pathological conditions including atherosclerosis,
inflammation, and tumor growth and metastasis. In the brain, the
endothelial cell wall, strengthened by tight junctions,
defines the blood-brain barrier (BBB). The extracellular matrix
molecules constitute the basement membrane underlying the vasculature
and play a critical role in maintaining the integrity of the BBB. After
focal stroke, there is a breakdown of the BBB with an associated
increase in vascular permeability, inflammatory cell influx, and
neuronal cell death. The present study was designed to investigate
the effects of MMP expression after stroke.
Methods—Focal stroke was produced by permanent middle cerebral
artery occlusion (MCAO) in the rat, and MMP protein expression was
measured by Western blot and zymogram analysis over a time
course ranging from 6 hours to 30 days (n=32). Immunohistochemistry at
1 and 5 days (n=8 and 6, respectively) was also utilized to
characterize the expression of several MMPs and related proteins after
stroke, including their cellular source. To test the hypothesis that
early increased MMP-9 expression is involved in ischemic brain
injury, a neutralizing monoclonal antibody directed against MMP-9 was
administered intravenously (n=7 per group) 1 hour before
MCAO, and infarct size was measured 24 hours later.
Results—MMP expression increased progressively over time after
stroke. After 12 hours, significant (P<0.05) MMP-9
activity was observed that reached maximum levels by 24 hours
(P<0.001), then persisted for 5 days at this level and
returned to basal (zero) levels by 15 days. On the basis of
morphological criteria, MMP-9 appeared to stain with
endothelial cells and neutrophils identified both
within and at the periphery of the infarct within 24 hours of focal
ischemia. After 5 days, MMP-9 appeared to stain with
macrophages present within the infarcted brain. MMP-2
activity was significantly (P<0.001) increased by 24
hours and was maximum after 5 days following MCAO. MMP-2 appeared to
stain with macrophages present within the infarcted region.
Unlike MMP-9 and MMP-2, tissue inhibitor of
metalloproteinase-1 was identified at comparable levels in both control
and ischemic tissue after MCAO. MMP-1 and MMP-3 could not be
detected in the brain after focal stroke. When an MMP-9–neutralizing
monoclonal antibody was administered systemically, animals exhibited
significantly reduced infarct size (ie, a 30% reduction compared with
non–immune antibody controls; P<0.05).
Conclusions—These results demonstrate that early increased MMP-9
expression in endothelial cells and infiltrating
neutrophils is a significant response to cerebral focal
ischemia and that selective inhibition of MMP-9 activity can
significantly reduce brain injury after stroke.
Department
of Neurology,
Johns Hopkins University School of Medicine,
Baltimore, Maryland
© 1998 American Heart Association, Inc.
Original Contributions
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats
Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size
Editorial Comment
Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size
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