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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 stroke. Its promise is blemished by the fact that tPA's brain-saving power fades fast after the third hour of a stroke, and then instead increases the risk of dangerous bleeding in the brain. But a recent study by Swedish and American scientists now show that these problems might be overcome, if a stroke patient first takes a drug currently used to treat leukemia.

The study, which is published online in Nature Medicine by scientists from University of Michigan Medical School and the Ludwig Institute at Karolinska Institutet, is performed on mice.

However, to test the theory in humans the researchers soon will begin a clinical trial in collaboration with the Karolinska University Hospital in Stockholm, using the leukemia drug known as imatinib (Glivec®).Their recent study on mice showed that the drug greatly reduces bleeding, even if tPA wasn't given until five hours after a stroke began.

"Ten years ago our research group identified the growth factor PDGF-CC, and we are now very excited having unraveled a mechanism in the brain involving this factor", comments the Karolinska Institutet team leader, Professor Ulf Eriksson. "This finding has indeed the potential to revolutionize the treatment of stroke."

The new paper details a series of molecular and cellular experiments conducted by the Swedish and American research 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 is 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.

Imatinib, however, inhibits the PDGF-alpha receptor permitting tPA to do its main job, which is to down clots that have lodged in the brain's blood vessels. If the clots are not removed, they will cut off blood supply and eventually starving brain tissue until it begins to die.

According to the World Health Organization (WHO), clots in the brain blood vessels causes 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.

"Our findings have immediate clinical relevance, and could be applied to find new treatments that will benefit stroke patients," says senior author, Professor Daniel Lawrence at the U-M Medical School. "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."

Funding for the study came from the National Institutes of Health, the Ludwig Institute for Cancer Research at Karolinska Institutet, the Novo Nordisk Foundation, the Swedish Research Council, the Swedish Cancer Foundation, the LeDucq Foundation and the Inga-Britt and Arne Lundberg Foundation.

Publication: 'Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke', Enming J Su, Linda Fredriksson, Melissa Geyer, Erika Folestad, Jacqueline Cale, Johanna Andrae, Yamei Gao, Kristian Pietras, Kris Mann, Manuel Yepes, Dudley K Strickland, Christer Betsholtz, Ulf Eriksson och Daniel Lawrence Nature Medicine, AOP 22 June 2008, doi 10.1038/nm1787.

For further information, please contact:
Professor Ulf Eriksson
The Ludwig Institute, Karolinska Institutet
Tel: +46(0)8-52487109
Mobil: +46(0)70-6805056
Karolinska Institutet is one of the leading medical universities in Europe. Through research, education and information, Karolinska Institutet contributes to improving human health. Each year, the Nobel Assembly at Karolinska Institutet awards the Nobel Prize in Physiology or Medicine.

Katarina Sternudd | idw
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