Three-pronged treatment in rats with lower spine injuries provides surprisingly impressive results
May 24, 2004
People with spinal cord injuries may one day regain the use of their limbs with a cocktail of treatments that proved extremely beneficial in rats with damaged cords, researchers say.
When tested two months after the three-pronged treatment, the animals, with lower spine injuries that damaged their hind legs, had more improvement than the scientists had ever seen. They walked 70 percent better than injured animals that did not have the combination treatment.
The study was designed by scientists at the Miami Project to Cure Paralysis and included three therapies: A medicine initially developed for depression; transplantation of Schwann cells that make myelin, the protective covering around axons, which are the long projections attached to cells that allow communication to take place throughout the body; and a medicine that increases the production of a messenger molecule called c-AMP. C-AMP signals genes to carry out specific functions.
Together, these treatments protected against further damage after the cord injury and allowed new axons to grow farther than expected. The study results appear this week in Nature Medicine.
"This represents a very significant finding," said Naomi Kleitman, program director for spinal cord injury at the National Institute for Neurological Disorders and Stroke in Bethesda, Md. "All of these strategies on their own have shown a benefit, but yield better results when combined."
Mary Bartlett Bunge, a professor of cell biology and anatomy and neurological surgery at the University of Miami School of Medicine, has spent 15 years coaxing cells in injured spinal cords to re-grow. This has seemed an almost impossible task.
Years ago, her late husband, Richard Bunge, and his colleagues developed the technique to take Schwann cells, which make the protective covering myelin, grow them in the laboratory and transplant them into the central nervous system, the brain and spinal cord. While Schwann cells don't normally grow in the central nervous system, when they are transplanted into it they promote nerve cells to regenerate in the damaged spinal cord.
"We've always believed that it would take a combination of treatments to tackle the many things that go wrong following a spinal injury," Bunge said.
A delicate balance
Rolipram is a drug initially developed for depression. It fell out of favor because of its troublesome side effects - nausea and vomiting. More recently, it's being tested in trials for multiple sclerosis. The drug works by preventing the breakdown of cyclic-AMP. C-AMP is in every cell in the body and increasing it can alter the inner workings of the cell. With more c-AMP present, genes are turned on to instruct the cell to grow.
The Miami Project strategy for combined therapy included an under-the-skin mini pump filled with rolipram that began delivering the medicine shortly after the spinal cord injury. One week later, Schwann cells (culled from the rat's leg and grown in a test-tube) were transplanted to the injured site. Then, they injected c-AMP into the spinal cord above and below the transplant.
Regulating c-AMP levels was key. Scientists knew that this messenger molecule decreases after an injury to the cord. The rolipram, which was infused for two weeks, prevented this decrease. Giving an extra shot of c-AMP made the levels of the molecule abundant at the site.
They found that more axons, the long extensions that carry the cell's message, survived with the combination therapy. In fact, there was 230 percent more surviving axons in the spinal cord and a 500 percent increase in myelinated axons in the area over the lesioned spine where the transplanted cells were injected. What's more, the axons grew beyond the graft, which is critical if cells are to reconnect with cells in the brain.
The animal's locomotion also was improved. They performed better on each of the three tests given to check the ability of their hind limbs to move.
Scientists are now repeating the studies to figure out the mechanisms behind the improvements, and to ensure that the new fibers don't contain pain signals, which could be detrimental if and when these treatments move into human trials.
The results of animal research are not always replicated in human studies.
But right now, there is a lot of research that holds promise for spinal
cord victims. Each year, 11,000 Americans injure their spinal cords. About
250,000 Americans are partly or completely paralyzed because of spinal
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