Scientists have made a key discovery that could lead to a new treatment for spinal cord injuries. Two research teams have found that a dose of a signaling molecule called cyclic AMP (cAMP) given before an induced injury causes damaged nerve cells to grow new fibers. This finding takes researchers a step closer to understanding and possibly treating paralysis in humans.
"The cAMP-treated neurons had obvious and extensive regeneration," says study author Marie T. Filbin, Ph.D., of the City University of New York in New York City. Normally, when an axon is severed, certain growth-inhibiting proteins, or "stop signals," prevent the axon from repairing itself. Filbin says cAMP seems to blind the cells to those stop signals, making conditions ideal for severed nerve fibers, or axons, to grow back.
Although the experiments were done in rats, researchers say the results may one day enable doctors to reverse paralysis in humans or treat other conditions resulting from spinal cord injuries. The National Institute of Neurological Disorders and Stroke (NINDS) funded the two studies, which were published in the June 13, 2002, issue of Neuron . 1,2
Sensory nerve cells are located near the spinal cord and their axons have two branches. One branch carries signals from the skin or other parts of the body to the cell. This fiber is a part of the peripheral nervous system. The other branch is a spinal cord fiber that carries sensory signals to the brain.
If the nerve fiber leading to the brain through the spinal cord is injured, inhibitory proteins normally prevent it from regenerating. However, in 1999, study author Simona Neumann, Ph.D., of the University of California at San Francisco, discovered that injuring the peripheral nerve fiber "primes" sensory nerve cells to grow by somehow helping them ignore the usual stop signals. Spinal cord nerve cells showed considerable re-growth if the spinal cord connection was severed within a week of the peripheral nerve injury. Researchers had previously shown this "priming" effect in optic nerve cells. Also in 1999, Dr. Filbin showed that raising cAMP levels within nerve cells at or before the time of injury enables these nerves to grow new fibers in laboratory dishes and to ignore the stop signals that prevent spinal cord regeneration.
The questions after these studies were, what happens in that first week after a peripheral nerve injury that stirs growth in the spinal cord, and what role does cAMP play in experimental animals? Two research groups, one led by Dr. Filbin and the other by Dr. Neumann and her colleagues, Allan I. Basbaum, Ph.D., and Marc Tessier-Lavigne, Ph.D., of UCSF, set out to find the answers.
The researchers injected cAMP into spinal cord nerve cells in rats, and then grew the cells in culture dishes along with proteins known to prevent regeneration. The nerve cells grew extensively in spite of the added inhibitory signals. Untreated cells barely grew at all. The scientists also gave rats infusions of cAMP, followed by an induced spinal cord injury a week later, and found that the sensory fibers in the rats' spinal cords grew beyond the injury site.
Dr. Filbin and her colleagues took the experiment a step further by intentionally stopping the action of cAMP to verify its role in blinding axons to stop signals. Their results show that an initial rise in cAMP occurs very early after the injury and programs the cells to grow. Blocking cAMP the day after the injury prevents regeneration, but blocking cAMP a week later does not influence nerve growth.
Although researchers now have a basis to begin investigating cAMP's effects in patients with spinal cord injuries, there are several reasons why the results of these experiments cannot immediately be applied to humans.
First, researchers administered cAMP directly to specific nerves before they were severed. Study author Dr. Tessier-Lavigne says testing the effects of cAMP after an injury is a very important next step in their research. "There is every reason to believe that administering cAMP after an injury would work as well, but that needs to be tested," he says.
Second, the researchers showed only that the axons regrew, not whether they were able to reconnect with target cells in the brain or spinal cord. And finally, this growth mechanism needs to be tested in motor nerve cells associated with paralysis. Dr. Tessier-Lavigne says sensory nerve cells are easier to reach with cAMP injections than motor nerve cells. "It was easier to obtain a proof of concept with those neurons. Clearly, we now must test other neurons, which are even more important from a therapeutic perspective," he adds.
One potential complicating factor in future clinical research is that cAMP stimulates a number of cell functions, says NINDS program director Naomi Kleitman, Ph.D. "If cAMP were given to humans, researchers would have to strongly consider the possibility of side effects, because cAMP could affect a lot more than just nerve cell growth," she said.
"While it is too early for clinical trials, these findings are promising and we can start thinking about possible drug therapies that would activate cAMP," says Dr. Kleitman.
2 Qiu J, Cai D, Dai H, McAtee M, Hoffman PN, Bregman BS, and Filbin MT. "Spinal Axon Regeneration Induced by Elevation of Cyclic AMP." Neuron, Vol. 34, June 13, 2002, pp. 895-903.