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Stroke Study Reveals a Key Target For Improving Treatment
Date:6/22/2008

Research in mice shows why tPA carries risks as well as benefits, and suggests that Gleevec or other drugs could prevent problems

ANN ARBOR, Mich., June 22 /PRNewswire-USNewswire/ -- For over a decade, the drug called tPA has proven its worth as the most effective emergency treatment for the most common kind of stroke. But its promise is blemished by two facts: tPA can cause dangerous bleeding in the brain, and its brain-saving power fades fast after the third hour of a stroke.

Now, a new paper published online in Nature Medicine reveals why tPA has these limitations. It also gives tantalizing evidence about how those problems might be overcome, if a stroke victim first takes a drug currently used to treat leukemia.

The researchers, from the University of Michigan and the Ludwig Institute for Cancer Research (LICR) Stockholm Branch at Karolinska Institutet in Stockholm, Sweden, emphasize that it's still too early to apply their findings -- made in mice -- to the treatment of stroke victims everywhere.

But the LICR-Karolinska Institutet team will soon begin a clinical trial to test the theory in humans, using the leukemia drug known as imatinib (Gleevec). In mice, that drug greatly reduced bleeding, even if tPA wasn't given until five hours after a stroke began.

The new paper details a series of molecular and cellular experiments conducted by the two teams, which began collaborating after hearing of each other's work.

They report that tPA apparently causes its risk of bleeding, and leakage of fluid within the brain, by accident. The culprit: tPA's tendency to act upon a protein called PDGF-CC, and the PDGF-alpha receptor that it binds to. This interaction causes the usually impervious "blood-brain barrier" to become porous, leading to leakage. Gleevec inhibits the PDGF-alpha receptor, apparently counteracting tPA's effect.

This unwanted effect on the blood-brain barrier appears to be unrelated to tPA's main job,
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SOURCE University of Michigan Health System
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