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| Robert Friedlander (left) and Ted Teng believe they have found a safe, new way to limit injuries to the spinal cord, vertebrae of which they hold. A common antibiotic, they discovered, reduces secondary damage caused by aftereffects from the primary injury, at least in rats. (Staff photo Jon Chase/Harvard News Office) |
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."
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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."