A combination therapy using transplanted cells plus two experimental drugs significantly improves function in paralyzed rats, a new study shows. The results suggest that a similar therapy may be useful in humans with spinal cord injury. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS)
, part of the National Institutes of Health, and appears in the June 2004 issue of Nature Medicine.*
About 10,000 people in the United States suffer spinal cord injuries each year. Studies in animals during the past decade have shown that supporting cells from nerves outside the brain and spinal cord, called Schwann cells, can be used to make a "bridge" across the damaged spinal cord that encourages nerve fibers to regrow. Other research has suggested that a substance called cyclic AMP (cyclic adenosine monophosphate) can turn on growth factor genes in nerve cells, stimulating growth and helping to overcome signals that normally inhibit regeneration. This study is the first to try a combination of the two approaches in an animal model of spinal cord injury.
In the new study, Mary Bartlett Bunge, Ph.D., Damien Pearse, Ph.D., and colleagues at the Miami Project to Cure Paralysis at the University of Miami School of Medicine, found that spinal cord injury triggers a loss of cAMP in the spinal cord and in some parts of the brain. They then transplanted Schwann cells into the spinal cords of rats in a way that bridged the damaged area. The researchers also gave the rats a form of cAMP and a drug called rolipram, which prevents cAMP from being broken down.
Treatment with the triple-combination therapy preserved and even elevated cAMP levels in nerve cells after injury. It also preserved many of the myelinated nerve fibers in treated animals, compared to untreated rats and those that did not receive the triple combination, the researchers found. Myelin is a fatty substance that insulates the nerve fibers and improves transmission of signals. The treated rats also grew back many more nerve fibers than untreated rats or rats that received only one or two of the therapies. The regenerated nerve fibers included many that carry the nerve-signaling chemical serotonin, which is important for locomotion.
Rats that received the triple therapy had much better locomotion and coordination 8 weeks after treatment than control rats.
"The behavioral improvements in the rats receiving the triple therapy are dramatically better than those reported previously using Schwann cell bridges or cAMP strategies in spinal cord-injured animals," says Naomi Kleitman, Ph.D., the NINDS program director for spinal cord injury research. Previous studies using Schwann cells found that nerve fibers from cells above the injury could travel onto the Schwann cell bridge, but they did not leave the bridge, she explains. The triple therapy "punches the cells into overdrive and helps them get off the bridge."
The therapies tested in this study were selected for their likely feasibility in humans, Dr. Kleitman adds. Rolipram has already been tested in clinical trials for other disorders, and Schwann cells can be grown from patients' own peripheral nerves.
The researchers are now planning follow-up studies to confirm their results and to try to learn more about how the triple therapy works, Dr. Bunge says. Their studies might also lead to the development of better drugs to prevent the breakdown of cAMP, she adds. http://www.ninds.nih.gov/