The clot-busting drug that for years has been used to treat heart attack and stroke patients has a surprising effect on brain cells. In the current Science, researchers report that tissue plasminogen activator (tPA) can protect neurons against toxic levels of zinc--a side effect of strokes that worsens brain damage. Although the finding has no immediate clinical significance, because tPA doesn't cross the blood-brain barrier to exert this protective effect, it may point the way to compounds that can limit stroke damage.
Ironically, neurologist Jae-Young Koh of the University of Ulsan College of Medicine in Seoul, South Korea, and his colleagues discovered tPA's new talent when they were investigating evidence that a protein it produces, called plasmin, can injure brain cells. Koh wondered if tPA might make neurons more sensitive to the high levels of zinc released in injured areas.
To their surprise, the scientists found that when they added tPA to their culture medium, brain cells were completely protected against the zinc that killed control cells. To test the molecule's role in animals, the team injected tPA into the cerebrospinal fluid of rats and then chemically induced seizures. Although the seizures were just as severe in the treated rats, fewer neurons died than in animals that received an injection of saline solution. However, when the scientists gave rats tPA intravenously--the way it is normally administered to patients--it had no protective effect, presumably because the drug didn't cross the blood-brain barrier.
Koh says that means it may be difficult to take advantage of the protection against zinc toxicity. Nevertheless, it is a "truly surprising discovery" that could hold valuable clues for drug development, says neurologist Dennis Choi of the Washington University School of Medicine in St. Louis.