Pathway from stroke to cell death Hopkins discovery may lead to first significant treatment

October 01, 1997|By Diana K. Sugg | Diana K. Sugg,SUN STAFF

Hunting down the damage stroke inflicts on the brain, neuroscientists at Johns Hopkins have followed the havoc all the way to the final step: They've figured out precisely how precious brain cells die.

To the scientists' surprise, they say they've found a common pathway, a few last steps that many dying brain cells must go through. The discovery may lead to the first significant treatment for stroke and may provide insights into other diseases like Alzheimer's and Parkinson's.

Published in the October issue of Nature Medicine, the finding explains how an often dormant enzyme that typically repairs DNA is thrown into overdrive, and depletes all the cell's energy, killing it.

"Everyone had hoped that there would be a magic bullet, a common final pathway. But I don't think anyone believed that it would exist," said Dr. Valina Dawson, the principal investigator and an associate professor of neurology at the Johns Hopkins School of Medicine. "We replicated the experiment several times to convince ourselves that this was real."

In the study, Dawson and other researchers first compared normal mice with mice genetically altered not to have the enzyme. After being exposed to brain toxins, the normal mice had lost about 65 percent of their brain cells. The mice without the enzyme didn't suffer any damage.

Scientists then induced experimental strokes in the two sets of mice. The results were so dramatic that researchers feared they had made a mistake: Tissue damage in the altered mice was 80 percent less than in the others.

Losing any brain tissue can change the way a person walks, talks and thinks.

Dr. John Hallenbeck, chief of the stroke branch at the National Institute for Neurological Disorders and Stroke, said the mechanism described by the Hopkins group is "novel," but noted that there are many factors involved in the damage.

"If someone can come up with a single mechanism that everything focuses down on and that explains all of this, that may be extraordinary," Hallenbeck said. "This may turn out to be that way, but rigorous work would have to be done to show that."

The finding is one piece in the revolution that has brought stroke from the backwaters of medicine to one of the hottest areas of research.

In the United States, stroke is the third leading cause of death and the No. 1 reason people become disabled. But there is no major treatment and, until recently, little hope. Doctors were consigned to monitoring a patient, waiting to see the extent of the damage. Strokes can steal vision or paralyze; they warp a person's words and scramble his thoughts.

But last year, the U.S. Food and Drug Administration approved for stroke a clot-busting drug widely used in heart attack cases. Called t-PA, the drug can reopen a blocked artery, restore blood flow and prevent fatal or disabling brain damage -- if administered within three hours of a person's stroke symptoms. Hospitals across the country are creating "brain attack" teams and trying to teach the public that in stroke, every minute counts.

At the same time, more than a dozen drugs are being tested that target different points in the chain of events that lead to cell FTC death. Called neuroprotectants, these medicines may eventually work with clot-busting drugs to get the blood flow going again and bring back damaged brain cells. But results of the neuroprotectants have been disappointing so far because patients suffered too many side effects.

The new finding caps years of tracing clues and analyzing the destructive sequence that starts when a blood vessel in the brain bursts or becomes clogged, cutting off the blood flow. This is a stroke. Surrounding cells are deprived of nutrients and oxygen, and they begin to die.

The cascade that follows goes something like this: Mechanisms designed to shut down one of the brain's neurotransmitters, called glutamate, don't work. Glutamate gets overactive, stimulating nitric oxide, which in turn start damaging the cell's DNA. This prompts an enzyme, called PARP, to step in and try to fix the DNA. But it gets overactive, and drawing on energy sources in the cell, uses them up. The cell dies.

This is one pathway from stroke to cell death. Scientists believe there may be many such pathways, but Hopkins scientists believe their newly explained one is key. They predict that stopping the PARP step, because it is further downstream than other points targeted, will have a major impact.

"If you block PARP, you block everything. It succeeded beyond our wildest imaginations. The reduction in stroke damage was greater than we believe has been seen with any treatment ever," said Dr. Solomon Snyder, director of Hopkins' department of neuroscience and one of the authors of the paper.

"I was frankly thunderstruck to realize that PARP explained it. It could have been so many other ways."

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