From the Departments of Neurology (G.A.R., E.Y.E., J.E.D.), Cell Biology
and Physiology (G.A.R.), and Neuroscience (G.A.R.), University of New Mexico,
Albuquerque, NM.
Correspondence to Gary A. Rosenberg, MD, Department of Neurology, University of New Mexico, Albuquerque, NM 87131. E-mail grosen{at}unm.edu
Background and
Purpose—Reperfusion disrupts cerebral capillaries, causing
cerebral edema and hemorrhage. Middle cerebral artery occlusion
(MCAO) induces the matrix-degrading metalloproteinases, but their role
in capillary injury after reperfusion is unknown. Matrix
metalloproteinases (MMPs) and tissue inhibitors to
metalloproteinases (TIMPs) modulate capillary permeability. Therefore,
we measured blood-brain barrier (BBB) permeability, brain water and
electrolytes, MMPs, and TIMPs at multiple times after
reperfusion.
Methods—Adult rats underwent MCAO for 2 hours by the suture
method. Brain uptake of 14C-sucrose was measured from 3
hours to 14 days after reperfusion. Levels of MMPs and TIMPs were
measured by zymography and reverse zymography, respectively, in
contiguous tissues. Other rats had water and electrolytes measured at
3, 24, or 48 hours after reperfusion. Treatment with a synthetic MMP
inhibitor, BB-1101, on BBB permeability and cerebral edema
was studied.
Results—Brain sucrose uptake increased after 3 and 48 hours of
reperfusion, with maximal opening at 48 hours and return to normal by
14 days. There was a correlation between the levels of gelatinase A at
3 hours and the sucrose uptake (P<0.05). Gelatinase A
(MMP-2) was maximally increased at 5 days, and TIMP-2 was highest at 5
days. Gelatinase B and TIMP-1 were maximally elevated at 48 hours. The
inhibitor of gelatinase B, TIMP-1, was also increased at 48
hours. Treatment with BB-1101 reduced BBB opening at 3 hours and brain
edema at 24 hours, but neither was affected at 48 hours.
Conclusions—The initial opening at 3 hours correlated with
gelatinase A levels and was blocked by a synthetic MMP
inhibitor. The delayed opening, which was associated with
elevated levels of gelatinase B, failed to respond to the MMP
inhibitor, suggesting different mechanisms of injury for
the biphasic BBB injury.
Department
of Neurology,
Washington University School of Medicine,
St Louis, Missouri
© 1998 American Heart Association, Inc.
Original Contributions
Matrix Metalloproteinases and TIMPs Are Associated With Blood-Brain Barrier Opening After Reperfusion in Rat Brain
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