Stroke Study Reveals a Key Target For Improving Treatment

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, which is to break down clots that have lodged in the brain's blood vessels, cutting off blood supply to the area and starving brain tissue until it begins to die.

Such clots cause 80 percent of the 15 million strokes that occur each year worldwide. Five million people die, and 5 million more are permanently disabled, by strokes each year, according to the World Health Organization.

"Our findings may have immediate clinical relevance, and could be applied to find new treatments that will benefit stroke patients," says senior author Daniel Lawrence, professor of cardiovascular medicine in the U-M Medical School and member of the U-M Cardiovascular Center. "By better understanding how the brain regulates the permeability of the blood-brain barrier, and how tPA acts upon that system, we hope to reduce the risks and increase the time window for stroke treatment."

Ulf Eriksson, the leader of the team at the Ludwig Institute for Cancer Research Stockholm Branch at Karolinska Institutet, comments, "Our research group identified the growth factor PDGF-CC 10 years ago and we are now very excited having unraveled a mechanism in the brain involving this factor, which potentially will be a revolution in the treatment of stroke. Together with our clinical colleagues at the Karolinska University Hospital in Stockholm we are now rapidly continuing to explore this exciting possibility in clinical trials involving stroke patients."

If the clinical trial in human patients in Sweden bears out the findings seen in mice, perhaps Gleevec could be given immediately upon suspicion of stroke-like symptoms, before diagnostic scans and other tests can be made to determine if a patient could benefit from tPA.

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