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