July 18, 2006 In tests on rats, researchers at Johns Hopkins and the University of Michigan have developed a treatment that helps spinal cord nerves regrow after injury. The findings will be published in the July 18 issue of the Proceedings of the National Academy of Sciences. The study has implications for treating people who may face amputation of an arm after a violent injury in which nerves are wrenched from the spinal cord. The new treatment currently is under study for other types of traumatic spinal cord injury.
The researchers treated experimental nerve injuries in rats with an enzyme - called sialidase - that they isolated from bacteria. Four weeks later, more than twice as many nerves in the spinal cords of sialidase-treated rats grew new nerve fibers compared to untreated rats.
The experimental injury in rats mimicked an injury in humans that may occur during childbirth or in motorcycle accidents when an arm is pulled violently away from the body. This injury causes nerves to be yanked out of the spinal cord. Without these nerves, the arm loses feeling and muscle tone. Without muscle tone, the body cannot support the weight of the arm, and many health problems can develop.
While surgeons can sometimes reattach the yanked nerves to the spinal cord, this treatment is not as effective as physicians or patients would like. This is in part because nerves in the brain and spinal cord, unlike those in the rest of the body, fail to grow new nerve fibers. Nerves in the brain and spinal cord are surrounded by signals from other cells in the injured area that stop them from growing.
"Molecules in the environment of the injured spinal cord are specifically instructing the nerve end not to regrow," says the study's director, Ronald Schnaar, Ph.D., professor of pharmacology and neuroscience in the Institute of Basic Biomedical Sciences at Hopkins.
"The brain and spinal cord are extremely crowded with nerves and nerve fibers, which may be why we have developed careful controls that tell cells to stop making new connections. The crowded central nervous system has ways to say 'OK, we're done' to keep nerves from sprouting willy-nilly and making inappropriate connections. But in gaining the ability to crowd nerves close together, we have given up flexibility - the ability to heal after injury."
"If you sever your finger, it can be surgically reattached, and nerve fibers typically grow back so that you can use your finger again," says Schnaar. "In contrast, the injured brain and spinal cord are rocky terrain for nerve fiber growth," he says. "Finding ways to smooth that road might help the nerve fibers to regrow."
Several molecules in the spinal cord are known to stop nerve fibers from growing. Schnaar refers to these molecules as axon regeneration inhibitors, or simply ARIs.
"Treatments that eliminate ARIs might allow the nerve ends to regain their natural regenerative abilities as they do in the periphery and improve recovery," says Schnaar.
The researchers looked at the boundary between the spinal cord and the periphery to see if they could coax a nerve end to grow out of the inhibitory spinal cord into a more permissive environment that contains fewer ARIs. They chose to mimic the injury commonly seen in motorcycle accidents, called brachial plexus avulsion, because it involves nerves at the boundary between the spinal cord and periphery.
The researchers surgically severed nerves that normally extend from the spinal cord to the shoulder of anesthetized rats. They then transplanted a nerve from the hind leg of the same animal into the spinal cord to reconnect the injured nerve ends.
To coax the injured nerve ends to grow fibers and connect to the transplanted nerve, they used an implanted pump to bathe the area with one of three different enzymes known to destroy ARIs. Four weeks after transplantation and enzyme treatment, the researchers injected dyes into the nerves to see whether and how many nerve fibers grew from the injured cells of the spinal cord into the transplanted nerve.
Rats treated with one of the three enzymes tested, sialidase, showed well over twice the number of new nerve fibers than rats treated with saline, which is not expected to enhance nerve growth. Moreover, the researchers saw that the new fibers were made by nerve cells residing in the spinal cord.
"We have established that the enzyme sialidase, which destroys one of the molecules that inhibits nerve regeneration, is sufficient to robustly improve nerve fiber outgrowth from the spinal cord," says Schnaar.
Surgical transplantation of a peripheral nerve to help nerve fiber growth from the spinal cord has shown limited success in humans. "The addition of a new treatment to enhance our current surgical management of brachial plexus avulsion in people would be welcomed by patients and surgeons alike" says Lynda Yang, M.D., Ph.D., an assistant professor of Neurosurgery at the University of Michigan. Dr. Yang, the study's lead author, helped pioneer the study of ARIs while a doctoral student with Dr. Schnaar at Johns Hopkins in the 1990s.
Having shown here that sialidase can increase the number of spinal cord nerve cells that extend fibers into a transplanted nerve, Dr. Yang now is testing if the nerves re-establish muscle control. "We're very interested in seeing how much function you can get back," she says.
According to Schnaar, there is some evidence that this transplant technique coupled with sialidase treatment can coax other, nearby nerve cells within the spinal cord to grow out as well. "Once you rewire, then the brain does an amazing job of sorting it all out," he says.
Having established the ability of sialidase to improve spinal nerve regeneration into transplanted peripheral nerves, Schnaar and his research team at Hopkins are testing the same treatment to see whether it will help nerve regeneration in other types of spinal cord injuries.
"Even a small improvement might mean a lot. People with spinal cord injuries generally are not looking to play football," says Schnaar, "but to regain basic functions. A modest improvement in nerve regeneration might make a big improvement in a patient's quality of life."
The researchers were funded by two branches of the National Institutes of Health: the National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute, and by the Department of Neurosurgery at the University of Michigan.
Authors on the paper are: Yang of the University of Michigan, and Ileana Lorenzini, Katarina Vajn, Andrea Mountney, Lawrence Schramm, and Schnaar all of Johns Hopkins.
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