Published Online
on July 10, 2003

A more recent version of this article appeared on August 1, 2003

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Submitted on March 21, 2003
Accepted on April 15, 2003

Closure of the Blood-Brain Barrier by Matrix Metalloproteinase Inhibition Reduces rtPA-Mediated Mortality in Cerebral Ischemia With Delayed Reperfusion

Thomas Pfefferkorn MD^* and Gary A. Rosenberg MD

From the Departments of Neurology (T.P., G.A.R.), Neurosciences (G.A.R.), and Cell Biology and Physiology (G.A.R.), University of New Mexico Health Sciences Center, Albuquerque, New Mexico.

^* To whom correspondence should be addressed. E-mail: thomaspfefferkorn{at}hotmail.com.

Background and Purpose--Intravenous recombinant tissue plasminogen activator (rtPA) can be beneficial in ischemic stroke despite an increased risk of hemorrhage and potential neurotoxic effects. We hypothesized that rtPA-mediated adverse effects depend on the timing of reperfusion and injury to the blood-brain barrier (BBB).

Methods--Male Wistar rats had middle cerebral artery occlusion (MCAO) by intraluminal thread placement. Intervals of ischemia/reperfusion, respectively, in hours were 0/18, 1.5/16.5, 3/15, 6/12, 18/0 and 6/1. Animals received either rtPA or saline for 1 hour at the time of reperfusion or, for the 18/0 trial, starting 1 hour after MCAO. Outcome parameters were mortality, matrix metalloproteinase-2 and -9 (MMP-2 and -9) concentrations, tissue hemoglobin, and brain water content. We analyzed the permeability of the BBB by using the brain ¹⁴C[sucrose] uptake method. Effects of the MMP inhibitor BB-94 on the BBB without rtPA treatment and on mortality with rtPA were tested in animals with 6/1 and 6/12, respectively.

Results--In delayed reperfusion (6/12), rtPA increased mortality from 17% to 83% (P<0.01) without significantly affecting other outcome parameters. In 6/1, sucrose uptake in the ischemic hemisphere was markedly increased (8.80±1.14% vs 2.15±0.26%; P<0.01). This uptake was reduced by treatment with BB-94 (3.95±1.48%, P<0.01). Furthermore, BB-94 reduced rtPA-mediated mortality in 6/12 to 33% (P<0.05).

Conclusions--rtPA-mediated mortality in delayed reperfusion is associated with early opening of the BBB. Closure of the BBB with BB-94 given before rtPA treatment reduced mortality, suggesting that treatment with MMP inhibitors might reduce the risk associated with thrombolysis.

Key words: blood-brain barrier • metalloproteinases • thrombolysis • rats

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