For release: Monday, August 12, 2002
A new study shows that a chemical naturally produced by the body helps improve motor skills after a stroke by stimulating undamaged nerve fibers to grow new connections in the brain and spinal cord. Researchers say that infusions of this chemical, called inosine, substantially improves brain function following strokes in rats.
The study suggests a new potential for stroke treatment amid ongoing research efforts.
"We're very excited that the effect of inosine, which we first saw in cell culture studies, can play out in the adult central nervous system, and lead to significant brain reorganization after stroke," says study author Larry Benowitz, M.D., a researcher at Boston's Children's Hospital and an associate professor of neurosurgery at Harvard Medical School.
The study was funded in part by the National Institute of Neurological Disorders and Stroke and appeared in the June 25, 2002, edition of the Proceedings of the National Academy of Sciences.
Strokes kill about 160,000 Americans each year, making stroke the third leading cause of death in the United States. It is also the leading cause of long-term disability in adults. The most common form of stroke occurs when a blocked blood vessel prevents blood flow to parts of the brain, depriving cells of oxygen and resulting in lost sensory or cognitive abilities, motor control, and/or speech. Some stroke victims gradually recover lost brain function, but the brain has a limited ability to repair itself.
Previous studies in rats showed that inosine is a potent promoter of axon growth in optic nerve cells. They also showed that inosine activates a cell signaling pathway that controls the expression of genes needed for axon growth.
In this new study, researchers induced strokes in rats by blocking a main artery that supplies blood to a part of the brain responsible for control of one leg. The result of the experimental stroke was a rat with one weak leg. Rats were given inosine infusions through pumps implanted into their brains for periods up to several weeks. A control group received saline infusions.
Rats treated with inosine performed much better than the untreated rats on tests of paw-placing ability, reaching for food and swimming. After 19 days, the treated rats had recovered about 90 percent of their paw-placing abilities lost to stroke, while untreated rats had about a 50 percent improvement in their abilities. While no untreated rats succeeded in retrieving food with their weak limbs, 50 percent of the inosine-treated rats retrieved food with their weakened limbs - when the other leg was constrained - by the fourth week of the experiment. The treated rats were also less inhibited when placed in water, paddling nearly twice as much as the untreated rats.
"The improvement in food retrieval was significant, since that's what the animals need to do in real life," Dr. Benowitz says. "In humans, this might be similar to picking up a utensil or holding a telephone, but certainly not playing the violin."
The study is one of the first to show that undamaged nerves can cross over the middle of the brain to make new connections with parts of the brain damaged by stroke. A previous study showed some crossing over by a different mechanism after spinal cord injury.
Researchers speculate that inosine may help neurons respond to axon growth signals sent out by areas of the brain that have lost their normal inputs.
"The significance of this study is that it shows the largest amount of rewiring after a stroke ever found in an animal model," Dr. Benowitz says. "Of course, its relevance to humans now needs to be demonstrated."
In future studies, scientists will look at the mechanism for inosine delivery. Inosine is quickly broken down in blood and the digestive tract, so it needs to be administered directly to the brain as an infusion, rather than given orally. "So far, the infusion is the only way we know that inosine can work," Dr. Benowitz says.
On the other hand, scientists speculate that inosine can be safely delivered. The rats did not appear to experience any side effects, and toxicity studies show that inosine does not cause any organ damage. "It's unlikely that inosine has any serious side effects, because it is naturally found in the body," Dr. Benowitz says. "But that would have to be tested in humans before we could say inosine is safe."
Benowitz and his team plan to conduct clinical trials to test the effects of inosine in humans. The trials will focus on treating people as soon as they are admitted to a hospital for stroke, because the animal studies show that inosine is most effective if given within the first 24 hours. "There may be some effect if treatment begins months or years afterwards, but we do not have any evidence that's the case," Dr. Benowitz says.
The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system.
Reference: Chen P, Goldberg DE, Kolb B, Lanser M, and Benowitz LI. "Inosine induces axonal rewiring and improves behavioral outcome after stroke," Proceedings of the National Academy of Sciences USA , Vol. 99, No. 13, June 25, 2002, pp. 9031-9036.
- By Tania Zeigler
Last Modified March 29, 2016