EMBARGOED By Proceedings of the National Academy of Sciences for 5 p.m. EST Monday, March 12, 2001
UCSD Researchers Discover Mechanism of Natural Recovery from Spinal Cord Injury
Findings Have Potential for New Therapies
Researchers have discovered that rats with spinal cord injuries show some motor-function recovery several weeks after injury based on spontaneous re-growth of spared nerves. This finding has potential to further advance recovery after spinal cord injury.
The research was conducted at the University of California, San Diego (UCSD) School of Medicine and the Veterans Affairs Medical Center, San Diego, and is described in the March 13, 2001 issue of the Proceedings of the National Academy of Sciences.
|The functional abilities of the rats were measured by a pellet retrieval
In the study, researchers removed 97 percent of the connections in the rat spinal cord that coordinate movement of the forepaw and foot. Despite this loss, rats gradually began to recover coordinated movements of their forepaws and by four weeks after the injury were no different from intact rats.
Study of their spinal cords under the microscope showed that a small proportion of nerve fibers spared by the original injury – only 3 percent – grew new connections to increase their number of contacts with other cells by 331 percent. Called sprouting, like the branches of a tree after pruning, this re-growth occurred spontaneously without therapeutic intervention. When the researchers prevented sprouting from occurring, functional recovery did not occur.
Because approximately 40 percent of humans who suffer spinal cord injury, stroke or head trauma also show spontaneous recovery of motor function, the researchers believe the present findings may explain their recovery. For example, most humans with spinal cord trauma have small rims of spared tissue-containing nerves at the injury site, and many of these individuals show partial recovery of function over weeks and months.
The UCSD investigators who conducted the study are now testing whether sprouting can be enhanced experimentally to lead to better recovery. By nerve-site delivery of nerve growth factors – proteins that stimulate nerve growth – the researchers will determine whether sprouting can be enhanced and lead to further recovery.
The current study was conducted in the lab of Mark Tuszynski, M.D., Ph.D., UCSD associate professor of neurosciences and a neurologist with the VA Medical Center. Based on their findings in rats, Tuszynski and his team are studying monkeys to determine if similar sprouting and functional recovery occur, and if potential therapies such as nerve growth factor can stimulate natural axon re-growth.
In the rat experiments, surgical lesions were made to the corticospinal tract, an important section of the spinal cord system, vital for controlling skilled motor acts such as movements of limbs in rats and hands and feet in humans. The researchers found that natural recovery of motor function in the rats occurred when some spinal cord tissue – as little as 3 percent – survived the injury.
In post-mortem views of the rats’ spinal cords, the researchers observed re-growth of axons from the intact portion of the corticospinal tract. The sprouting “probably accounts for the improvement in function that occurs in humans weeks to months after spinal cord injuries, strokes or head trauma,” Tuszynski says.
However, when the corticospinal tract was completely severed in the rats, the researchers observed neither sprouting of axons nor functional recovery of motor skills.
The researchers made lesions in the rodents’ neck area, since most human spinal cord injuries occur in the cervical, or neck region. Several variations of lesions were made, to determine where and how the spinal cord was affected, and to measure the degree of recovery of functional motor skills.
One group of rats had lesions made to the dorsal, or upper back region of the spinal cord that contains 97 percent of corticopinal axons. Another group had lesions to the ventral, or upper front side, that contains about 3 percent of total axons. A third group received a dorsal lesion followed five weeks later by a lesion to the ventral component. Both ventral and dorsal regions were severed at the same time in a fourth group of rats, while a fifth group received a lesion of the medullary region, which causes an effect similar to severance of the ventral and dorsal regions together.
The functional abilities of the rats were measured by a pellet retrieval task. Prior to the surgeries, the rats were trained daily to extend their forepaws, grasp a food pellet, retract the limb and eat the pellet. Following surgery, researchers took precise measurements of the animals’ ability to perform these tasks. Measurement of axonal sprouting was obtained with post-mortem studies of the spinal cord neurons and axons.
Following complete lesions of the dorsal region, spontaneous sprouting occurred in the uninjured, considerably smaller ventral tract, and the number of new axonal connections increased by 331 percent. With the sprouting, the rats experienced extensive recovery of hand movement.
No functional recovery was noted in three groups – the rats with an initial dorsal lesion, followed five weeks later by a ventral lesion; the rats with both dorsal and ventral components severed at the same time; and the group with a medullary lesion.
In addition to Tuszynski, authors of the PNAS paper were UCSD Department of Neurosciences researchers Norbert Weidner, M.D.; Arvin Ner, B.S.; and Nima Salimi, B.S.
The work was funded by the National Institutes of Health, Veterans Affairs, the Canadian Spinal Research Organization, the Swiss Foundation for International Research into Paraplegia on behalf of the Sandoz Family Foundation, and the Hollfelder Foundation.
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