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Molecule Rewires Brain After Stroke

Rat study on inosine hold promise for people

MONDAY, June 24, 2002 (HealthDayNews) -- A natural molecule found in food and over-the-counter supplements may be the first drug that can help the nervous system rewire itself in the aftermath of a stroke or other brain damage.

When infused into rat brains, the compound, called inosine, spurs the growth of healthy neurons to bypass dead spots left in the wake of surgically induced brain attacks, a new study says. These fibers, which restore missing electrical impulses necessary for proper movement and other functions, help the animals regain at least some lost performance on a variety of behavior tests.

"What inosine is doing is getting fibers on the good side of the brain to form new connections to the spinal cord," says Larry Benowitz, a Harvard University neuroscientist and a co-author of the study. "These guys aren't going to be able to play a piano concerto, but they might be able to swipe at something or retrieve food that that they'd not been able to before."

Existing stroke therapies try to prevent additional damage after episodes of blood loss to a region of the brain. "But they don't have any effect on stimulating the intact brain to form new connections," Benowitz says.

The research was funded in part by Boston Life Sciences, a biotech company that hopes to bring inosine therapy to human stroke patients. The company is now planning a study testing the drug in people, and with regulatory approval will begin the trial early next year.

Dr. Mark Lanser, the company's chief scientific officer, says the substance must now be administered as an infusion directly into the brain because it is quickly broken down in blood and by the gastric system. It's also too big to penetrate the blood-brain barrier that protects the organ from large molecules.

However, Lanser says that if clinical studies show promise, the firm would try to develop a version of inosine that can be taken orally or by injection. Boston Life Sciences would also like to test the compound in patients with spinal cord injuries and head trauma.

An estimated 750,000 Americans suffer strokes each year, and 160,000 die from them. The debilitating events occur when blood flow to the brain is interrupted, either by a ruptured or blocked blood vessel.

Inosine is a precursor to adenosine, a key player in a variety of body functions, from the creation of DNA molecules to the generation of energy. The chemical, found in brewer's yeast and organ meats like liver and kidney, has been touted as an exercise aid, though its record as a performance enhancer has fallen flat.

Still, the new work, published in tomorrow's issue of the Proceedings of the National Academy of Sciences, suggests a more important agenda for the chemical.

In earlier findings a team led by Benowitz, who heads a research lab at Children's Hospital Boston, showed that inosine prompts animal neurons in a dish to extend their axons. Axons are the long tendrils that link brain cells. How this works isn't entirely clear, but the substance seems to switch on genes that go dormant in adult animals, he says.

This time, Benowitz's group sought to learn what happens to brain cells bathed in inosine after surgical strokes that kill off many millions of neurons.

The researchers performed the operation on two groups of rats, leaving them severely impaired.

Within about three weeks of the stroke-inducing procedure, untreated rodents showed a 50 percent improvement in one standard test of mobility that measures paw reaching.

However, during the same period the animals that received continuous inosine infusions regained nearly complete function on the test. They also made impressive strides on other exams that included swimming and grasping for food.

Treated animals began outperforming the untreated rats by the seventh day of testing, and progressively gained ground on them throughout the study. However, it's not clear if the benefits increased with time or if those gains were simply the echo of a one-shot boost, Benowitz says. "More research will be needed to establish the optimal procedures for treatment," he adds.

Whatever the case, tissue samples taken at the end of the performance studies showed that the treated animals had substantially more spreading of axons into parts of the brain deprived of their usual connections.

Benowitz says it's difficult to quantify the difference, though it appears to be three to five times as much axon growth as in the untreated rodents. While that constitutes only a small fraction of the original hookups, it's enough to spark the improvements in behavior.

Results his group obtained in recent weeks show treatment must also start within a day of a stroke to be effective. Why is something of a mystery, Benowitz says, because the compound acts not on the organ's deadened region but on the remaining healthy neurons.

Dr. Lawrence M. Brass, a neurologist at Yale University School of Medicine and a spokesman for the National Stroke Association, says the work could make a "huge impact on reducing the burden of stroke on patients and on society."

Brass said inosine "really represents a different approach than we've been using for the last couple of years," and reflects a shift in thinking about the brain.

As a medical student, Brass says, he was taught that the brain's major wiring is set at birth. However, as this study and previous work reveal, the brain sprouts new cells throughout its life, and those cells can form meaningful connections with other neurons.

"It's not just new wires that grow from [and to] nowhere. That's what is really exciting," he says.

What To Do

To learn more about inosine, try BlueCross. For more on strokes, visit the National Stroke Association.

SOURCES: Larry Benowitz, Ph.D., associate professor, neurosurgery, Harvard Medical School, Children's Hospital, Boston; Marc Lanser, M.D., chief scientific officer, Boston Life Sciences Inc., Boston; Lawrence M. Brass, M.D., professor, neurology, Yale University School of Medicine, New Haven, Conn.; June 25, 2002, Proceedings of the National Academy of Sciences
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