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Why Is This Stroke Drug So Dangerous?
23 June 2008 (All day)
A stroke drug known as tPA, or tissue plasminogen activator, has been a lightning rod since it was first approved in the United States in 1996. Although studies have found that the drug can reduce the brain damage wrought by strokes, it can also cause potentially fatal bouts of cerebral bleeding. Now a team of researchers has identified one reason for tPA's ill effect. And it turns out that in mice, the problem can be eased by administering a cancer drug.
TPA works by dissolving blood clots. That helps to restore blood flow to the brain after a stroke, potentially preventing additional brain cells from dying. tPA is only recommended if it can be given within 3 hours of a stroke; otherwise, doctors deem that the drug will do more harm than good, causing hemorrhages in the brain.
One clue to why tPA can cause bleeding came several years ago. Vascular biologist Daniel Lawrence of the University of Michigan, Ann Arbor, found that in mice the drug appeared to damage the blood-brain barrier, a membrane that protects brain cells from toxins in the rest of the body. Soon after, in an entirely separate study, molecular biologist Ulf Eriksson and colleagues at the Karolinska University Hospital in Stockholm, Sweden, found a new target of tPA: a molecule called platelet-derived growth factor-CC (PDGF-CC), which helps drive blood vessel formation. Why this might matter wasn't clear at the time, however, and it did not seem connected to tPA's clot-busting power. But drugs often have more than one molecular target, including targets not relevant to the diseases they're designed to treat.
In the new study, Lawrence and Eriksson teamed up and put the pieces together. They considered whether the role of PDGF-CC might help explain not tPA's benefits, but its harms--namely its risk of uncontrolled bleeding. They began by trying to better understand the function of PDGF-CC by giving it to healthy mice. The molecule made the mice's blood-brain barrier more permeable, just as tPA did. The researchers suspected that tPA's deleterious effect on the blood-brain barrier occurs because the drug happens to activate PDGF-CC, which also weakens the blood-brain barrier.
As it turns out, there's a drug on the market that neutralizes platelet-derived growth factors: Gleevec, which was designed to treat chronic myelogenous leukemia. To find out whether Gleevec would block PDGF-CC and minimize bleeding from tPA caused by damage to the blood-brain barrier, the team induced strokes in mice and gave some animals Gleevec. Five hours after the stroke--outside the recommended window--all animals were given tPA. Gleevec didn't eliminate the harmful bleeding, but it substantially reduced it: Those who received Gleevec had 50% less blood in their brain than those that got tPA alone, the team reports online this week in Nature Medicine.
Stuart Lipton, a neurologist and director of the Del E. Webb Neuroscience, Aging and Stem Cell Research Center in San Diego, California, says the study is "convincing" and sheds light on the bleeding associated with tPA. Eriksson and others in Stockholm are preparing to launch a clinical trial to test whether Gleevec given to a person suffering from a stroke might extend the window for supplying tPA. "We want to know very quickly if this translates into people," says Lawrence.