Combination Therapy Overcomes Spinal Injuries in Rats
Research could offer insights into such injuries in humans
FRIDAY, May 28, 2004 (HealthDayNews) -- New research that restored significant mobility to paralyzed rats offers hope -- albeit distant hope -- to the 243,000 Americans living with spinal cord injuries, experts say.
"This is quite exciting news, certainly to people with spinal cord injuries, their families and the health-care professionals who care for them. But we have a long way to go," said Dr. Kristjan Ragnarsson, chairman of rehabilitation medicine at Mount Sinai Medical Center in New York City. "Experiments in rats don't always translate very quickly into anything in humans."
Using a novel three-step approach, scientists succeeded in restoring up to 70 percent of normal walking function to the paralyzed rats. The animals received a combination of cell transplants along with two different medications. The result: They also had better foot placement, stability while walking, and coordination of front and back legs, the researchers said.
The study was conducted at the Miami Project to Cure Paralysis, a comprehensive spinal cord injury research center at the University of Miami School of Medicine. The research appears in the June issue of Nature Medicine.
Considerable attention has been focused on trying to restore mobility in people with spinal cord injuries by regrowing nerve cells, but, so far, success has been elusive.
"It is very difficult to bridge the gap between the normal section of the spinal cord over the injured part and into the part below which is relatively normal," Ragnarsson explained. "We have suspected for a long time that the inability of neurofibers to grow across this gap is related to a very hostile terrain."
The issue of "hostile terrain" around the damaged area of the spine proved key to the new study.
"The work that transformed the field of spinal cord repair showed in 1980 that nerve cells in the central nervous system do have the capacity to regrow, but it depends upon their environment," said senior study author Mary Bartlett Bunge. She is a faculty member of the Miami Project to Cure Paralysis and a professor of cell biology and anatomy and neurological surgery at the University of Miami School of Medicine. Bunge designed the study with colleague Dr. Damien Pearse.
Bunge's group at the Miami Project had previously shown that Schwann cells from the peripheral nervous system resulted in new nerve fibers when transplanted to the spinal cord.
"Schwann cells are formed into a cable that acts as a bridge to span the injury site. The bridge provides a supportive and growth-promoting scaffold for the regrowth of nerve fibers," Bunge explained. "The nerve fibers grew on to the bridge [of animals in the 1980 study], but they did not leave it to grow into the spinal cord in the appropriate location."
Other researchers have since discovered that the reason for this lack of growth may have been inadequately low levels of a "messenger molecule" called cyclic adenosine monophosphate (cAMP). Levels of cAMP dropped precipitously in the rats in the new study immediately after they were injured.
For the new study, the researchers first injured rats in the thoracic region of the spinal cord, which resulted in paralysis to the legs. Bruising is the most common form of spinal cord injury among people. An estimated 10,000 Americans suffer such injuries every year.
For two weeks, Bunge and her colleagues injected rolipram, which has been used as an antidepressant in humans and in clinical trials for multiple sclerosis. "The administration of rolipram prevents that initial drop in cAMP," Bunge said.
One week after the injury, the researchers transplanted by injection 2 million Schwann cells into the bruised area of each rat's spinal cord and, at the same time, injected cAMP into the areas above and below the transplant area. The rolipram prevented the breakdown of cAMP so it could accumulate in the animals. The levels of cAMP rose with the triple combination treatment, the researchers said.
The result was an impressive restoration in the ability of the animals to walk.
"This is the best strategy that we have found so far, the best result I have seen in 15 years of very hard work," Bunge said. "I think a combination strategy is gong to be very important because the reactions in spinal cord tissue after injury are many and varied, and therefore there are many issues to be considered and addressed in designing an effective strategy."
While it's too soon for human application, the new research contains some promising aspects.
"In all our work we try to conduct our experiments in a relevant way to human spinal cord injury," Bunge said. "For example, the Schwann cells we transplant are always from an adult animal, comparable to using an injured person's own Schwann cells."
The next steps involve replicating the study in different animals and understanding what amounts of rolipram and cAMP are most effective and when they should be given for optimal results.
In the meantime, a one-step approach might help. "We have quite a bit of preparatory work to do before going to a clinical trial, but I think it may be possible to use rolipram by itself because we did see a good effect with rolipram alone," Bunge said. "I want to be cautious, though. I don't want people in a wheelchair to say I'm going down there [Miami] next week. We have to be very well prepared so that we don't do more damage than good."