Nature's Own Medicine

Natural compounds shrink strokes and aid recovery

By William J. Cromie

Gazette Staff

Growth factors found in the brain show promise for limiting damage from strokes and for speeding up recovery afterwards.

Given within hours of a stroke, or "brain attack," one compound apparently shrinks the stroke, reducing its size by 50 percent in animals. Tests in human patients have already begun.

Newer and more exciting results show that this and another growth factor, given days after a stroke, help animals regain functions that were lost to strokes. Trials with people are expected to begin within a year.

"Growth factors are nature's own medicine," says Seth Finklestein, associate professor of neurology at Harvard Medical School. "Present in the brain and other parts of the body, they keep cells alive and promote their growth. If the body uses them in that way, why can't we?"

Finklestein sees growth factors as a new type of double defense against the third leading killer of Americans after heart disease and cancer. Someone in the United States suffers a stroke every 53 seconds and someone dies from one every 3.3 minutes.

Most strokes result from clots blocking blood vessels in the brain. Drugs known as "clot busters" may unblock vessels but, to be effective, must be given within three hours of the attack.

Growth factors, also given within a few hours, work by reducing the number of brain cells killed by a lack of the oxygen carried in blood. In experiments carried out at Harvard-affiliated Massachusetts General Hospital in Boston, cell death was reduced by 50 percent when mice and rats received basic fibroblast growth factor (bFGF) within three hours.

The medicine was then tested in 46 patients and found to be safe for human use. Further developed and manufactured by Scios, a biotechnology firm, and Wyeth-Ayerst, a pharmaceutical company, it is now being tested in human stroke victims under the trade name "Fiblast."

A Plumbing Problem

Although 500,000 to 700,000 Americans suffer strokes each year, two out of every three survive. According to the American Heart Association, 4 million stroke survivors are alive in the U.S. today.

As time passes many of these people, including those with stroke-induced paralysis and loss of speech, experience partial recovery. They regain some use of speech and other cognitive functions, as well as more use of arms and legs that may have been partly or fully paralyzed. Such recovery comes from undamaged parts of the brain taking over the functions of dead and damaged cells.

"A stroke is a plumbing problem, but it wrecks the house," says Finklestein. "However, the brain has its own ways to remodel undamaged parts in order to compensate for the injury. We've done experiments with animals showing that the brain naturally increases its production of two growth factors following a stroke. We reasoned that we could 'juice up' this effect by adding these factors to the spinal fluid. It worked."

Finklestein and his colleagues used either bFGF or something called osteogenic protein-1 (OP-1). Both drugs helped rats recover the use of fore- and hind legs incapacitated by strokes.

Previously, scientists discovered that bFGF enhances growth of skin and other connective-tissue cells in both animals and humans. OP-1 does the same for bone cells. Later, both factors were also found in the brains of lab rats and people.

"In stroke recovery, we think growth factors promote the sprouting of extensions from undamaged brain cells, which enables them to make new connections with other cells," Finklestein says. "Think of it as one cell throwing a pitch to the catcher's mitt of another. The pitch is a long thin extension that hits a target on another cell and forms a new connection. Such hookups build new circuits and networks in the brain; it's the same process nature uses for learning new facts and skills."

Exciting Possibilities

After 24 hours, nothing can be done to limit damage from a stroke. However, bFGF and OP-1, given days later, apparently enhance the recovery process, at least in rats. Finklestein is working with Creative Biomolecules, a Massachusetts company, to set up safety and efficacy trials of OP-1 in humans.

"There's the real and exciting possibility that we may be able to help people with drugs given days, even weeks, after a stroke," Finklestein says.

Results so far indicate that bFGF and OP-1 are equally effective.

"They appear to work by slightly different mechanisms," Finklestein explains. Fiblast makes brain cells extend themselves -- the pitching part of the game. OP-1 makes the catcher's mitt grow larger, increasing chances of the pitch reaching home plate. It may turn out that it's best to use them together.

There's also the possibility of using Fiblast in a protective/preventive mode. "It might be kept ready during brain surgery for head injuries or aneurysms -- ballooning weak spots in brain arteries," Finklestein suggests. "It also could be kept at hand when people at increased risk for stroke undergo heart surgery."

Growth factors are a hot area of research. bFGF and vascular endothelial growth factor (VEFG) are under investigation for growing new blood vessels around clogged arteries in the heart and legs.