Monday, March 29, 2004

Drug limits spinal cord damage

Antibiotic reduces cell death in spinal injuries

A common antibiotic used to treat arthritis and acne shows promise for limiting the severity of spinal cord and brain injuries.

When a fall, car crash, bullet, or knife crushes or cuts a spinal cord, the injury does not stop there. Rather, tissues continue to discharge toxic chemicals for hours, even days and weeks. These chemicals kill and disable nerve cells some distance away from the core injury, compounding the damage and making rehabilitation more difficult or impossible.

Putting together clues about how brain and other nerve cells die, Yang (Ted) Teng and Robert Friedlander, Harvard Medical School neurosurgeons, decided to try to limit such the damage with an antibiotic called minocycline. Working with colleagues at Brigham and Women's Hospital and Children's Hospital, and the Veterans Administration in Boston, they gave rats injections of the drug one hour after spinal injuries that caused them to lose the use of their hind legs.

The hind limbs of rats that did not get the drug remained paralyzed. In contrast, animals that received minocycline could walk with their hind legs supporting their weight and stand in a way that is close to normal. Their reflexes were better than those of the untreated rats. When placed head down on an inclined board, treated rats held their positions at angles that caused the other rats to slide off. Moreover, the treated rats showed less scarring and increased survival of nerve cells vital for passing signals along their spinal cords.

"We conclude that the anti-cell death, anti-scaring and anti-inflammatory effects of this drug are primary factors for reducing the secondary damage of spinal cord injuries," says Teng, a Harvard Medical School assistant professor of surgery who specializes in studying such injuries. "These results are exciting because they demonstrate a novel strategy in the form of a safe substance that could serve as a prototype drug for developing better treatments for people suffering from spinal cord injuries."

Although approved by the Food and Drug Administration for other uses, minocycline has to be tested on humans with spinal cord injuries before it can be used for this purpose. Once so approved, it might be given by emergency room doctors and field personnel, such as military medics and emergency medical technicians.

"If minocycline, or a similar drug, is successfully tested in humans, people like Christopher Reeve would be the kinds of patients it would be ideal for," notes Friedlander, an associate professor of neurosurgery at Harvard Medical School. (Reeve, a well-known actor, became paralyzed from the neck down after falling from a horse.) "In such devastating cases, any small benefit resulting from drug treatment could greatly improve the quality of life."


Opening the window

Friedlander began studying enzymes that cause brain cell damage in 1997. He noted that minocycline works in blunting the painful inflammation of rheumatoid arthritis by blocking one of these nasty proteins. He also became aware that researchers in Finland had successfully used the drug to reduce the size of strokes in rats.

Further investigation in his lab revealed that minocycline works in a cell's energy generator, a place called the mitochondria. "Think of the mitochondria as a nuclear reactor," he says. "Certain enzymes throw a monkey wrench in its works, and this activity can produce molecules that play a role in rheumatoid arthritis, acne, stroke, and Huntington's disease [a genetic malady caused by degeneration of nerve cells in the brain]."

Friedlander focused on a molecule called cytochrome c, and Teng reasoned that monocycline could dampen secondary damage caused by the activity of this molecule. The two then did the rat experiments that proved they were right. Teng, Friedlander, and their colleagues describe the details of these experiments in the March 5 issue of the Proceedings of the National Academy of Sciences.

Their work showed that the peak time for release of noxious cytochrome c is between four and eight hours after damage that does not completely sever the spinal cord, a situation that occurs in about 90 percent of such injuries. "We don't know yet the details of how it is released," Friedlander admits. "But once it is, it's a sure sign that cells are about to die."

"The four-to-eight hours gives us a window to work in," Teng explains. "Until now, all experimental treatments had to be given within 15 minutes of the primary injury. That's usually not enough time to get someone to an emergency room, or even into an ambulance. With this new window, we have a better chance of halting the secondary tissue death."

"Our next step is to see how far we can open the window," Friedlander adds. "We started giving minocycline one hour after the injury. Maybe we can extend it to two hours, giving us more time to work before and after the injury is treated."


Human trials

Teng, Friedlander, and their colleagues are not plowing this field alone. Two groups of researchers in Canada and one in South Korea have reported successful experiments using minocycline in animals. Friedlander says that one of the Canadian teams, at the University of Calgary, plans to start testing the drug in humans.

The U.S. Army is interested in the potential of minocycline. In combat situations, severe spinal cord injuries are often easy to detect because victims lose movement of their arms or legs. With a window of one hour or more, properly trained military and civilian emergency technicians might be able use minocycline to significantly reduce the toll of paralyzing damage.

No evidence exists that minocycline can help regenerate spinal cord tissue. Research on regeneration going on in Teng's lab, for example, uses stem cells to induce replacement nerve fibers. But making the paralyzed walk again will be a long shot for many decades. In the meantime, a drug like minocycline could still help in injuries that some paraplegics describe as "worse than dying."

"Even when a cord gets completely severed, you still have the cascade of secondary tissue death," Teng points out. Reducing this damage could have a deep impact on rehabilitation.

The spinal cord boasts some built-in tolerance, that is, you don't need all of its functions all of the time to control your arms and legs. Rehabilitation works on this loophole. However, secondary effects can damage nerve filaments far from the core injury, partly or completely closing the loophole. "Even if rehab can lead to movement in one finger instead of none, that can be a relatively big step," Teng notes.

After-injury nerve degeneration may also produce continuous pain, muscle spasms, and skin problems. Teng sees this as "another area where we hope drugs like minocycline will increase the quality of life for those who survive severe spinal damage."

By: William J. Cromie ~ Harvard Gazette
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Wednesday, March 17, 2004

Containing the Damage of Spinal Cord Injuries

Nerve cell proteins may help reduce disability in days after injury

New findings from animal studies on nerve cell proteins show promise for reducing disability after someone suffers a spinal cord or other nervous system injury.

That finding comes from a Wake Forest University Baptist Medical Center study in the current issue of Cell Stress and Chaperones.

The Wake Forest researchers found they could prevent up to 50 percent of motor and sensory nerve cell death in mice with sciatic nerve injury. They did this by augmenting the stress protein response, in which cells produce proteins called Hsc70 and Hsp70.

These proteins help protect motor and sensory nerve cells from death when the cells are exposed to heat, injury or other forms of stress that threaten them.

"Our approach is based on a natural mechanism cells have for protecting themselves, called the stress protein response," lead researcher and neuroscientist Michael Tytell says in a prepared statement.

"We believe it has potential for preventing some of the disability that occurs as a result of nervous system trauma and disease," Tytell says.

The research is aimed at preventing or minimizing the secondary cell death that occurs in the hours and days after a spinal cord or brain injury. During this period, cells surround the injury site can become inflamed and die. This cascading response worsens the injured person's degree of disability.

By: Robert Preidt - HealthDayNews
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Saturday, March 13, 2004

Scientist's work may aid with paralysis, head injuries

By CLAUDIA FELDMAN ~ Houston Chronicle

A local researcher has advanced the search for cures for central nervous system injuries by using a naturally occurring substance produced in the body to eliminate scar formation and promote nerve regeneration.

'It's major,' says Stephen Davies, who hopes the seeds of his research one day will help patients with paralysis and head injuries.

Davies' work with rats and the anti-scarring agent called decorin was published earlier this week in the European Journal of Neuroscience. He says decorin, administered directly to the spinal cord injury with a tiny pump, suppressed inflammation and scar formation. Decorin also provided a hospitable environment for new nerve fibers to grow, pass through the injury site and keep growing.

Without the decorin, Davies found the scar tissue presented a physical and molecular barrier to nerve fiber growth.

'In our experiments we eliminated the formation of scars, and we were thrilled, ' said Davies, an assistant professor of neurosurgery and neurosciences at Baylor College of Medicine. 'For the past 100 years, the scar has been a major obstacle. We hope this gives us a new treatment in our armory to repair the spinal cord.'

The next steps, the researcher said, are to better understand how decorin functions, to determine whether the rats recover from their spinal cord injuries, and to transfer the rat experiments to sheep. Davies says it's important to see if he can replicate his results in large mammals, which more closely resemble human patients than rodents.

If all goes exceedingly well, Davies says he will apply for FDA approval to use decorin in patients in the next three to four years.

If all goes exceedingly well, Davies says he will apply for FDA approval to use decorin in patients in the next three to four years.

"We have to make sure it's as safe as we think it is," he says. "All of this will take time. I don't want to give anyone false hope, but we are moving along as fast as we're allowed to go."
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Treatment Could Help Paralysis Patients

Atlanta Will be Home to New Procedure
By: Diana Davis, Health Reporter

ATLANTA -- In what could be a major breakthrough, a metro Atlanta research center is embarking on a new research project that, when complete, could help restore movement to some paralysis patents.

The Shepherd Center, a non-profit specialty hospital in Atlanta that works with patients who have suffered spinal cord injuries, brain injuries, multiple sclerosis and other neuromuscular illnesses and urological problems, has announced the start of a $3.2 million, grant-funded effort that includes the construction of a cell processing center.

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The initiative is being underwritten by a grant from the Marcus Foundation, and early results from the procedure appear promising.
The cell processing center will allow doctors to extract cells from an injured patient's own body before they are injected back into the person's spinal cord.

Doctors say movement has returned to about 30 percent of paralysis patients who have undergone the procedure.

Meet Jason Richardson

Eight months ago, Jason Richardson was paralyzed from his chest down after suffering a diving accident.

'I was told about the procedure six days after my injury,' he said.

Some 10 days later, Richardson was in an operating room in a hospital in Tel Aviv, Israel and became one of the first patients in the world to have the groundbreaking procedure. During the surgery, specially processed cells from his body were injected back into his spine.

He said the sensations he thought he had lost forever returned within days after the surgery.

"Once you've had that taken away from you, words can't explain how important it is when it come back," Richardson said.

While 30 percent of patients like Richardson have shown improvements after the treatment, the number drops to between 2 and 5 percent for people who don't have the new procedure.

Richardson was told he would likely never be able to move his hands or arms. Now, however, he can.

The procedure developed in Israel is coming to Atlanta. During a press conference to announce the grant from the Marcus Foundation, researchers said the procedure works by essentially tricking the body's nerve cells to regenerate.

Doctors say the method is a milestone that represents a huge advance because the patient's own specially processed blood and skin cells fuel the recovery.

"They go in and clean up some of the debris (and) some of the dead tissue but it's also thought that they help release what's called a nerve growth factor (which) promotes the actual growth of new tissue," said Mike Jones, a vice president at the Shepherd Center.

Doctors say they are cautiously optimistic about the benefits that could occur. And yet, Richardson said it's hard to fathom the improvements he has made.

"It's no where near real to me yet," he said.

Doctors say the new treatment is only effective in patients whose injuries are recent. The procedure should occur within 10 days after the injury.

Researchers say the difficult task now is to make sure that doctors and local hospitals are aware of the procedure so that patients can get treated in time.
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Easing the Agony of Spinal Cord Injuries

Neurotoxin reduces pain in rat study

A potent neurotoxin eliminated pain-transmitting rogue nerve cells responsible for chronic pain in rats after they suffered paralyzing spinal cord injuries.

University of Florida scientists report their finding in the online edition of Neuroscience Letters.

This approach is called molecular neurosurgery. The neurotoxin acts on specific sites in the spinal cord, where the neurotoxin is incorporated into nerve cells, which then die.

Eliminating these nerve cells let the scientists greatly extend the time between spinal cord injury and signs of pain behavior in the rats. It also decreased the severity of pain experienced by the rats.

This research may help scientists better understand the mechanisms of pain suffered by people after a spinal cord injury. Up to 80 percent of people who suffer a spinal cord injury develop some form of chronic pain at or below the level of their paralysis.

'Most people think spinal cord injury results in a loss of sensations below the level of injury, but it turns out that spontaneous pain following spinal injury usually is referred to parts of the body below the level of injury, where there is no motor or sensory function,' Robert P. Yezierski, director of the Comprehensive Center for Pain Research, says in a prepared statement.

'The unfortunate thing is we have no long-term effective treatments for this type of pain. This is why we are trying to develop novel approaches. We think that molecular neurosurgery could potentially be an answer for this condition,' Yezierski says."
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Reduced scarring helps nerves grow through spinal injuries

Infusing a naturally occurring anti-scarring agent called decorin into the damaged spinal cords of rats suppresses key molecules that block nerve regeneration after spinal cord injury, said Baylor College of Medicine (BCM) researchers in a study published today in the European Journal of Neuroscience.

The researchers are the first to use decorin to suppress inflammation and scar formation in spinal cord injuries. "Scar tissue that develops at sites of injury stops the regeneration of connections in the adult central nervous system," said Dr. Stephen Davies, lead author on the study and an assistant professor of neurosurgery and neurosciences at BCM. "Infusion of decorin into spinal cord injuries prevents the formation of proteoglycan rich scar tissue by suppressing inflammation."

Misaligned scar tissue that forms at spinal cord injuries physically blocks nerve regeneration and contains molecules called chondroitin sulfate proteoglycans that inhibit nerve fiber growth. Decorin inhibits the action of pro - inflammatory molecules released in spinal cord injuries, called transforming growth factors, which are thought to promote the formation of scar tissue.

Researchers in the study infused decorin directly into the injury site in rats with a mini-pump system, which used silica cannulas 160 microns in diameter. Because the cannulas were so small, they did not contribute to the formation of scar tissue. Using a high-powered laser scanning microscope and protein chemistry to analyze tissue samples, Davies and co-workers were able to show that decorin infusion reduced inflammation, scar formation and the levels of some proteoglycans by 80-95 percent allowing nerve fibers (called axons) to grow across spinal cord injuries in just four days.

"We have found a promising new approach to control inflammation and scar formation, which will be an important part of future strategies to encourage axon regeneration and recovery after spinal cord injury," Davies said.
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