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Illustration of woman's back showing the spinal columnRegenerating Hope:
Spinal Cord Research at UK

by Debra J. Gibson

Imagine scattering a bunch of computer parts on a table, leaving the room for a while, and the parts magically assembling themselves into a functional computer. On the much more sophisticated level of neuron growth in a fetus, this is roughly how the nervous system develops.

During fetal development, the nervous system generates several billion neurons, and these neurons make trillions of connections. Within the spinal cord—the largest nerve in the nervous system—millions and millions of individual cellular wires form little bundles. Operating independently and following what neurologists call guidance proteins, each bundle makes specific connections to different regions and cell populations in the brain.

The spinal cord is the physiological equivalent of a smart cable connecting the body to the brain—your CPU. All the sensory information your body gathers travels to your brain through this cable, and all the information your brain translates travels back through the spinal cord, which assigns this information to specific muscles. It's an ingeniously complex system that allows us to stand, move, turn, and bend.

Most of us take these actions for granted—but not the approximately 11,000 people in the United States who suffer from spinal cord damage each year as a result of accident or disease. If the neurons in the spinal cord don't fire properly, the brain gets less information to translate, and in the case of severe injury, no information at all; so it can't relay instructions to the muscles. The location of the injury is important, too: the higher it is on the vertebral column—the closer it is to the brain—the more it limits what a person can do and feel.

Just a decade ago scientists believed that little could be done to help a person with a spinal cord injury. They thought that once damaged, neurons could not be repaired. This view changed in 1990 when a high dose of intravenous methylprednisolone, administered within eight hours after injury, was shown to improve motor function. Methylprednisolone, a synthetic steroid which has been used for the last half-century primarily as an anti-inflammatory agent, is the only drug currently approved to treat spinal cord injury.

Today, the University of Kentucky is well on its way to becoming a leader in spinal cord research. The Spinal Cord and Brain Injury Research Center (SCoBIRC) was established here in 1999 to encourage multidisciplinary research, and last July nationally known researcher Ed Hall, who is credited with developing high-dose methylprednisolone therapy, was named to head the center. He joins 20 faculty members and a team of research assistants and clinicians from a variety of disciplines who are studying every aspect of spinal cord injury, work that one day may revolutionize the way physicians treat these injuries.

Photo of Edward HallEdward D. Hall, UK's new director of the Spinal Cord and Brain Injury Research Center (SCoBIRC), discovered that high-dose methylprednisolone was effective in the treatment of acute spinal cord injury, and today it is the only drug approved for the treatment of this injury. UK established SCoBIRC in 1999 to promote studies that might ultimately lead to a functional repair of the injured spinal cord and brain. The center is funded in part by the Kentucky Spinal Cord and Head Injury Research Trust (KSCHIRT), which receives $12.50 from each speeding ticket fine to help pay for spinal cord and head injury research. "Kentucky has made a real commitment in this area through KSCHIRT," Hall says. "Because of the excellent faculty already in place and the commitment of the university and the state of Kentucky, UK is the best place imaginable to pursue research aimed at spinal cord and brain injury."

Limiting the Damage
James Geddes, an associate professor in the Department of Anatomy and Neurobiology at UK, focuses his research on the crucial hours following a spinal cord injury. "We can't prevent the initial damage which occurs milliseconds to seconds after the incident, long before emergency personnel arrive, but we can try to limit the damage in the hours that follow," Geddes says.

Secondary events to the injury are responsible for much of the damage to neurons, he says. One such event is calcium overload, which results in the activation of calpain, an enzyme that is triggered by elevated levels of calcium and then begins chewing up cellular proteins. However, because a certain level of calpain is important to normal cell function, Geddes doesn't want to block it completely.

Photo of James Geddes"We can't prevent the initial damage which occurs milliseconds to seconds after the incident, but we can try to limit the damage in the hours that follow."
—James Geddes

"Currently, we don't have good calpain inhibitors that can walk this fine line," he says. "And the ones we have must be injected directly into the tissue and are only active for about two hours, so you have to keep re-injecting them."

Geddes is in the early stages of developing an improved inhibitor that will be 10 times more potent than current inhibitors and possibly be given in pill form, making it easier for emergency personnel to administer. He is using synthetic calpain inhibitors as well as gene therapy to control the level of calpain in the spinal cord. A combination of calpain inhibitors with other therapeutic approaches, including antioxidant treatments and anti-inflammatory interventions, could effectively limit the secondary damage following injury.

Geddes predicts that combined therapies targeting specific mechanisms will offer greater neuroprotection and functional improvement than the currently approved treatment, the use of the synthetic steroid methylprednisolone. "But this drug," he says, "doesn't target calpain. There are drugs available that do inhibit calpain, but they aren't specific for it. And unfortunately, high concentrations of these drugs are required for them to work."

Reestablishing Lost Function
George Smith, an associate professor in the UK Department of Physiology, is interested in the chronic phase of a spinal cord injury—a few weeks later when the person's condition has somewhat stabilized. He hopes that his research will lead to ways to help people reestablish lost function.

"During the acute phase of the injury—a few hours to weeks—the neurons die a slow, progressive death," Smith says. "My lab studies the later stage of injury, after all the cells have died and the injury has reached a steady state. We want to go in and try to induce the axons to re-grow and reconnect, to try to get the wound to heal appropriately." Axons are nerve fibers that, like wires, extend long distances to connect one nerve cell to another.

Photo of George SmithGeorge Smith, an associate professor in the UK Department of Physiology, is interested in the chronic phase of a spinal cord injury—a few weeks later when the person's condition has somewhat stabilized. He hopes that his research will lead to ways to help people reestablish lost function.

Smith says there are several potential reasons why axons fail to regenerate. One mechanism is as old as the body itself—the overproduction of inhibitory molecules that are important to the healthy segregation of axons during fetal development and that stop axons from growing in the adult.

He explains that some of these molecules that are produced during development may be reactivated after a traumatic injury. "For instance, scientists know that meningeal cells, non-neuronal cells that cover the brain and spinal cord, actually migrate and infiltrate the wound after an injury to form scar tissue. But these and other non-neuronal cells also express some of the inhibitory molecules that may restrict axon growth."

Smith's research is focused on reducing this inhibition. "We're trying to neutralize the inhibitory molecules produced by these cells or prevent their migration into the wound cavity. We're also trying to find molecules that bind to the inhibitory molecules and inactivate them or make them switch sides, from an inhibitory molecule to a growth-supportive molecule," he says.

Smith is also involved in transplant targeting. His goal is to understand the mechanisms that lead to axon guidance and develop a therapeutic intervention to entice severed axons to re-grow to precise locations. To do this, he uses recombinant adenoviruses, replication-defective viruses used as a vehicle to transfer genetic material into nerve and glial cells (non-neuronal cells in the brain). Using this method, he can create a pathway to direct the growth of axons, and he has already had some noted success in this aspect of his work.

"We establish pathways," he says. "If the axons follow the pathway, they turn and grow toward the target. When we use certain molecules and set up a certain expression pathway, we can get axons to grow across one hemisphere of the rat brain. When they get to the other side of the brain, 50 percent turn and go into the striatum." The striatum is a part of the brain associated with Parkinson's disease.

"We're now developing a strategy to get all of them to turn. This is something nobody has done. No one has been able to get axons to grow along a specific pathway and make a discrete pathway decision (to turn into the striatum) in the adult human brain."

Smith is also developing microfilaments, which are thinner than a human hair and that can be used to provide a growth-supportive conduit that extends across a lesion gap. In collaboration with colleagues at U.T. Southwestern Medical Center in Dallas, he has developed a technology for fabricating FDA-approved polymers that dissolve over time and, as they dissolve, slowly release drugs. This tissue-engineering technology has broad applications, including wound healing within the spinal cord, as well as in other tissues.

"Here you have a very complicated system that is broken," Smith says. "Well, I've always liked the challenge of fixing broken things, and regeneration is a very intriguing challenge."

Improving the Quality of Life
While Smith is focused on long-term strategies to rebuild function, James Abbas, formerly in UK's Center for Biomedical Engineering and the Department of Physical Medicine and Rehabilitation and now at Arizona State University, is using current technology to help improve the quality of life for those with a spinal cord injury. With his research team at UK, he was involved in a pre-clinical trial using a neuromuscular stimulation device about the size of a pager that can help people with spinal cord injuries stand. Nationwide, 12 people have the implanted device, which was developed at Case Western Reserve University and the Cleveland Veterans Affairs Medical Center.

Here's how this device works: It is surgically implanted in the person's abdomen, and eight electrodes from the device are attached to muscles in the upper legs and lower back. When the person wants to stand, he or she activates the device with an external trigger. It sends an electrical signal via radio frequencies to the stimulator, which causes the muscles to contract and allows the person to stand.

Some 10,000 Americans sustain spinal-cord injuries every year from car accidents (44%), gunshot wounds or other violence (24%), falls (22%), or sports (7%), largely diving.

Abbas is quick to point out how important this seemingly simple movement is. "One of the biggest potential complications for people with a spinal cord injury is pressure sores," he says. "Some people don't have a lot of padding between the bone and the skin. When someone is sitting, pressure between the bone and the seat can cause a sore to develop under the skin. This can happen very quickly, in a matter of minutes. If these sores get bad enough, the person can end up in a hospital for months while the sore heals."

Being able to stand could greatly reduce this problem. It could also enable those with a spinal cord injury to transfer from a wheelchair without help, improve their muscle tone, and give them the ability to reach for items. In short, it increases their independence, often boosting self-esteem as well.

And this is merely a starting point as far as the potential capabilities of this system. "For the past several years, we've been focusing on how we can make the system more functional, trying to come up with ways that will allow people to use their hands more and stand longer," Abbas says.

But even such a basic system is an exciting advance for many, including Alexander "Sasha" Rabchevsky, an assistant professor in the Department of Physiology at UK and one of only two people in Kentucky with the implanted device.

"I had a motorcycle accident in the summer of 1985 when I was 19," Rabchevsky says. "Ironically, it was just a week before my football camp started. [He was a stand-out high school football player.] There's no doubt that my spinal cord injury from that wreck drove me into the field of neuroscience. Before the accident, I was a pre-med student in college, but with a 2.2 GPA," he laughs. "After the accident, armed with a sharpened interest, I brought this up in one semester to a 3.0—even after missing an entire academic year for rehabilitation."

Rabchevsky had the operation last January, and he says that an important factor in deciding to have the surgery was because one of the surgeons who would operate on him, Deborah Blades, was a colleague and personal friend. After coming to UK in 1993, she worked with Rabchevsky (and Stephen Scheff, a professor in the Department of Anatomy and Neurobiology) on several research projects.

Photo of Sasha Rabchevsky and Deborah BladesSasha Rabchevsky, an assistant professor of physiology at UK, is one of only two people in Kentucky with an implanted neuromuscular stimulation device that can help people with spinal cord injuries stand. Deborah Blades is the UK neurosurgeon who performed the implant surgery.

"I really enjoyed collaborating with Sasha and Stephen," Blades says, "but my interest was always in making the leap from the laboratory to clinical applications. I had worked extensively on functional-electrical stimulation during my residency at my alma mater, Case Western, so that's how it all came together with Sasha."

Blades says that Rabchevsky's operation, which was done at Case Western, took a lot less time—12 hours—than she and the medical staff in attendance had thought it would. The procedure involved making 13 incisions at eight different points in the body and attaching electrodes to various muscle groups from the device itself, which was implanted in the abdomen. "Things just moved so smoothly that day," she says, "it was great. And all the way through, Sasha's been an outstanding patient—the best!"

Since his operation, Rabchevsky has not only been able to stand for longer and longer periods of time, but has also been able to take his first steps since the accident 17 years ago. He says that the greatest motivating factor in deciding to have the implant was so that he could stand up and kiss his wife, which he says was a "fine moment."

Combining Therapies
Rabchevsky undergoes therapy each day and works out to maintain his athletic physique, but he spends most of his time in the lab, attacking the problems of spinal cord injury under a microscope. Most of Rabchevsky's research involves combinational therapies, meaning that he is looking for ways to use the innate mechanisms of the body along with various drugs to enhance healing processes in the spinal cord. The ultimate goal is functional recovery after injury.

Recently, the compound he has been working with is basic fibroblast growth factor, or bFGF. He is attempting to use this drug in combination with standard methylprednisolone treatment in order to prevent the spread of the initial damage throughout the spinal cord. "What we're trying to do, using rats as a model, is use a drug that has been shown to be beneficial for cell survival and growth—bFGF—and combine it with what is now being used clinically, methylprednisolone. Our hope is that the two will work synergistically to further improve recovery," Rabchevsky says.

Illustration of spine"Interestingly, rats with a spinal cord injury can gradually walk over time—not completely normally, but they can walk—whereas a human with a similar type of injury can't," he says. "We are trying to tap into whatever mechanisms rats have that allow them to do that. If we can figure out what the mechanisms are, perhaps we can apply it to human beings."

Autonomic dysreflexia (abnormal autonomic reflexes) after a spine injury is also a major focus for Rabchevsky. With this condition, there is no descending influence from the brain, and the autonomic nervous system goes haywire: the system below the injury is ready to go, but there's no command.

"When normal bodily reflexes go unchecked, any painful sensation to the body below the level of injury—even something as minor as an ingrown toenail—can lead to elevated blood pressure, a lowered heart rate and a serious state of anxiety. The brain can't send any messages down the spinal cord to settle the unconscious nervous system," he explains.

Rabchevsky cites the example of a professional football player named Derrick Thomas, who was paralyzed from a car accident. Two weeks after the accident, during his recovery, he was being transferred from his bed to a chair. He had an autonomic dysreflexia episode, had a heart attack, and died.

"This was a healthy 33-year-old, six-time Pro Bowl athlete in the NFL," he says. "Nobody really knows why this occurs, or why it occurs only in people with high thoracic spinal cord levels of injury but not lower levels. So I am studying the possible mechanisms and nerve pathways that may contribute to this life-threatening condition."

Rabchevsky's research on dysreflexia involves injecting adenoviruses, replication-defective viruses, into injured spinal cords of rats. These viruses can be designed to encode special growth factors as well as growth inhibitors that may alleviate autonomic dysreflexia after a spinal cord injury.

He is also very interested in a cell called microglia.

"It's a unique cell in the central nervous system," Rabchevsky says. "It's very enigmatic because people don't know exactly what its normal function is. When the central nervous system is disturbed—from disease or trauma—microglia are immediately activated and they mobilize to the site of injury. For many years, people associated them with the bad guys: 'Look, there's death and destruction, and there's microglia.' But it turns out that microglia might be the good guys, trying to augment self-repair processes. My work, along with the work of others, has shown that microglia in the injured rat spinal cord are actually pro-regenerative. They potentially secrete molecules that can actually help guide regenerating axons.

"Again, this a combinational approach," he says. "I want to extend my initial studies and fully characterize how microglia help to promote regeneration in the injured spinal cord.

"There's not going to be a magic bullet," he says of treatments and methods used to study spinal cord injuries. "It's not going to be one answer or one intervention. We have to attack this problem through multidisciplinary approaches, incorporating basic investigations into the cellular and molecular mechanisms that translate into improving the quality of life for those who are paralyzed."

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