By stimulating nerve cells in laboratory rats at the time of the injury and then again one week later, the scientists were able to increase the growth capacity of nerve cells and to sustain that capacity. Both factors are critical for nerve regeneration.
The study, reported in the November 15 issue of the Proceedings of the National Academy of Sciences, builds on earlier findings in which the researchers were able to induce cell growth by manipulating the nervous system before a spinal cord injury, but not after.
Key to the research is an important difference in the properties of the nerve fibers of the central nervous system (CNS), which consists of the brain and spinal cord, and those of the peripheral nervous system (PNS), which is the network of nerve fibers that extends throughout the body.
Nerve cells normally grow when they are young and stop when they are mature. When an injury occurs in CNS cells, the cells are unable to regenerate on their own. In PNS cells, however, an injury can stimulate the cells to regrow. PNS nerve regeneration makes it possible for severed limbs to be surgically reattached to the body and continue to grow and regain function.
Regeneration occurs because PNS cell bodies are sensitive to damage to their nerve processes, and they react by sending out a signal that triggers the nerve fibers to regrow, explains Allan Basbaum, PhD, senior study author and chair of the UCSF Department of Anatomy. "Apparently this communication doesn't take place within the CNS."
Scientists do not yet know the biochemical cause for the difference, he adds.
The traditional scientific approach in efforts to enhance CNS regeneration is to manipulate the biochemical environment of the cells at the site of the spinal cord injury, according to Basbaum. Instead of this type of investigation, Basbaum's team used nervous system manipulation techniques to apply the principles of PNS cell growth capability to CNS cells.
The researchers took advantage of an unusual class of nerve fibers that has both a PNS and a CNS branch. Previously, the researchers had shown in animal studies that an injury made to the peripheral branch prior to a spinal cord injury provided the essential communication signal that enabled the CNS branch to grow. But this only worked if the PNS injury--which served as priming for CNS cell growth--was made at least a week before the CNS injury. "Clearly this would have no utility in clinical situations, where treatments cannot be made in anticipation of spinal cord injury," says Basbaum. Another challenge the researchers faced was stimulating CNS cells to grow beyond the injury site and into healthy tissue, which is essential to help regain function.
"A PNS injury at the time of spinal cord damage will only promote growth of nerve fibers into the spinal cord lesion, but not into the tissue beyond it. This is because growth capacity is enhanced, but it is not sustained," he explains. In the new study, researchers evaluated the effect of two peripheral nerve lesions (injuries) in animals with spinal cord injury. One lesion was made at the time of the cord injury and a second was made a week later. Both lesions were located in the animals' sciatic nerve, which is part of the PNS.
The researchers found that the two "priming lesions" not only promoted significant spinal cord regeneration within the area of the spinal cord injury, but more important, the regenerating axons grew back into normal areas of the spinal cord, where the hope is that functional connections can be reestablished. Axons are the long, fragile, fibers that conduct impulses between nerve cells in the brain, spinal cord and limbs.
"Getting the growth beyond the lesion is key. If we can get those axons to grow even a few centimeters past the lesion, they can start sending signals and developing new circuits throughout the body," says Basbaum. Basbaum adds that timing is critical for successful nerve regeneration. "There is a window of opportunity just after the injury when the potential for growth through and beyond the lesion is greatest. If we wait too long after an injury, the cells revert back to their normal, no-growth state. Plus, scar tissue begins to form, making growth difficult." "These findings give us hope. The nervous system is capable of being modified to a level where we can achieve nerve fiber growth. Ultimately, the goal is to promote growth and sustain it long enough for recovery of movement to occur in spinal cord injury patients," he concludes. Study co-authors include first-author Simona Neumann, PhD, and Kate Skinner, MD, both of UCSF. The research was funded by the Roman Reed Spinal Cord Injury Research Fund of California and the National Institutes of Health.
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