Combination Therapy Dramatically Improves Function
After Spinal Cord Injury in Rats
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 Medicine¹
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.
The NINDS is a component of the National Institutes of Health within
the Department of Health and Human Services and is the nation's
primary supporter of biomedical research on the brain and nervous
system.
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