Most Effective Emergency Stroke Treatment Drug May
Get Even Better with a Little Help
Benefits from tPA increased by leukemia drug,
imatinib (Gleevec) in tests
June
23, 2008 - 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.
Five million people die, and 5 million more are
permanently disabled, by strokes each year, according to the World
Health Organization.
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.
According to WHO, 80 percent of the 15 million
strokes that occur each year are caused by the type of blood clots in
the brain that tPA can dissolve.
Today, less than 3% of patients with this type of
stroke receive tPA, because the narrow safety window has often passed by
the time a stroke patient reaches a hospital and is diagnosed. If the
planned clinical trial with stroke patients in Sweden confirms the
findings of the present study, there is great promise that imatinib or
similar drugs could be administered to stoke patients to increase the
therapeutic window of tPA.
“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
for Cancer Research Stockholm Branch at 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, Ludwig Institute for Cancer Research,
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.
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