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Halting a Stroke Villain

Strokes inflict 80% less brain damage in mice that lack a DNA repair enzyme, according to a report in this month's issue of Nature Medicine. In normal mice, the zealous enzyme robs brain cells of energy--by trying to repair damaged DNA--for hours after a stroke. The finding suggests that an inhibitor of the enzyme might prevent damage in humans after existing drugs have restored blood flow.

During a stroke, blood flow to part of the brain is cut off--along with its supply of oxygen and nutrients such as sugar. Most stroke research has focused on restoring oxygen to the brain, says Valina Dawson, a neuroscientist at Johns Hopkins University. But research has shown that brain cells continue to die after blood flow is restored, since renewed metabolism generates free radicals that damage DNA and other parts of the cell. In response, cells activate an enzyme called poly(ADP-ribose) polymerase (PARP) to repair DNA damage. Dawson reasoned that in trying to repair the cell's DNA, PARP might seriously deplete energy resources and perhaps even kill the cell.

Dawson and her team looked first at cell cultures from the brains of mice who were bred not to produce PARP. Even when these cells were deprived of oxygen and sugar, or exposed to chemicals that release neurotoxins such as nitric oxide, they were not damaged--although up to 65% of cells from normal mice died when subjected to similar treatment. When the researchers then induced stroke in mice either with or without the PARP gene, they found that the resulting tissue damage in the mice without the enzyme was 80% less than in normal mice. "The protection was phenomenal and beyond our best expectations," Dawson says. Most animal testing of drugs has achieved between 10% to 30% less damage, and sometimes up to 50%, she adds.

The protective effect of PARP inhibition is "striking" and makes "a very strong case" for examining the role of PARP in human stroke, says Thomas Jacobs, a neuroscientist at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.