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Stroke study reveals key target for
improving treatment
Newswise — 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 at the
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 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, Ph.D., 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, Ph.D., the leader of the team
at the Ludwig Institute at the Karolinska
Institutet, comments, “Our research group
identified the growth factor PDGF-CC ten
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.”
Eriksson and Lawrence collaborated with a
number of colleagues — including lead author
Enming Joe Su, Ph.D. of U-M and teams at the
University of Maryland and Emory University
— to perform the study.
Some of the mice in the study lacked the
natural tPA that the body makes on its own.
Some of the mice underwent a procedure that
simulated the effects of a clot-based, or
ischemic, stroke.
The researchers first demonstrated in
non-stroke mice that tPA and PDGF-CC
appeared to act on the same target, but that
to cause the blood-brain barrier to leak,
they both had to be injected directly into
the brain side of the barrier. So, something
else must be causing tPA to produce this
effect when it is delivered through the
bloodstream, which is how it is given during
stroke treatment.
That’s where the PDGF-alpha receptor comes
in. The team looked at the activation of
these receptors in the side of the brain
where a stroke occurred, compared with the
other side, in both normal mice and mice
that were deficient in natural tPA. This
experiment confirmed that the receptor is
crucial to the blood-brain barrier
permeability that is caused by tPA
activation of PDGF-CC.
Knowing that imatinib is a drug that
inhibits the PDGF-alpha receptor, the
researchers then tested the drug’s effect as
a preventive agent.
First, they induced strokes in the mice,
then gave some of the mice a dose of
imatinib one hour after the stroke began.
The mice that received the drug had 33
percent less leakage than those that didn’t,
and 72 hours later, the mice that received
imatinib had 34 percent less damage to the
brain than the others.
Finally, the researchers tested the effect
of imatinib as a pre-treatment to be given
before tPA, to protect against bleeding in
the brain. They gave imatinib to mice one
hour after the stroke began, and then waited
until five hours had elapsed after the start
of the stroke before giving tPA.
The level of bleeding in the brain was
measured by assessing the amount of
hemoglobin in the stroke-affected side of
the brain. Mice that had received imatinib
before tPA had 50 percent less hemoglobin
than those that had not received
pretreatment.
This last experiment is especially
encouraging for its potential to be
translated into clinical practice, says
Lawrence. Stroke diagnosis often takes
hours, especially if a patient delays
getting to the hospital or needs to be
transferred to a hospital that offers
diagnostic brain scans and tPA treatment.
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.
Funding for the study came from the National
Institutes of Health, the Karolinska
Institutet, the Novo Nordisk Foundation, the
Swedish Research Council, the Swedish Cancer
Foundation, the LeDucq Foundation and the
IngaBritt and Arne Lundberg Foundation.
The study’s authors include Linda
Fredriksson, Melissa Geyer, Erika Folestad,
Jacqueline Cale, Johanna Andrae, Yamei Gao,
Kristian Pietras, Kris Mann, Manuel Yepes,
Dudley K Strickland, and Christer Betsholtz.
Reference: Nature Medicine, DOI
10.1038/nm1787
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