How Do You Mend A Broken Brain?

In August, 1986, John Breeding, then 23, took his pickup out for a spin along the dirt roads of rural Delaware. Racing around a corner, he hit a drainpipe at the side of the road and flipped over into a ditch. With his head caught between a partially open window and the truck's roof, his neck snapped. When paramedics arrived, Breeding had no feeling from his neck down--he was effectively a quadriplegic.

Two days later, at the Shock Trauma Center at the Maryland Institute for Emergency Medical Services in Baltimore, Dr. Fred H. Geisler began treating him with an experimental drug called GM-1. The results were startling: After two months, "I started feeling my toes," says Breeding. And from then on, he began regaining motion. Now, his left side is nearly normal, and he has some function in his right arm and leg. With a brace he can walk, drive, swim, and "even mow the lawn," he says. "If I hadn't gotten the drug, I would have been paralyzed from the neck down."Just a year ago, there was only anecdotal evidence that any drug could help prevent paralysis caused by spinal-cord injuries. But last May, researchers announced a new use for an old drug called methylprednisolone: It can limit damage when given within the first few hours after a spinal-cord injury. And now, in a study headed by Geisler that appeared in the June 27 issue of The New England Journal of Medicine, GM-1, made by Fidia Pharmaceutical Corp. in Italy, was shown to significantly enhance the recovery of half of the 16 patients receiving the drug. Like Breeding, most of those were able to function much better than untreated patients just six months after being injured. "For the first time, we've been able to move neurological recovery from the laboratory into clinical practice," says Geisler, chief of neurology at the Columbia Medical Group in Columbia, Md.

Perhaps even more striking, the same drugs that are showing such promise in spinal-cord injury are also being investigated--along with a half-dozen others--to treat stroke and head injuries. That's potentially a much larger market. Only 10,000 Americans suffer spinal-cord injuries each year, but nearly 400,000 suffer strokes, the third-largest killer in the U. S. An additional half-million incur serious head injuries in accidents. The market for a drug that would treat such problems is estimated at upwards of $2 billion a year in the U. S. alone. In addition, there is evidence that some of these drugs may also be helpful in halting the progression of such degenerative ailments as Alzheimer's and Parkinson's disease. "It's becoming very clear to drug companies that there is a halo effect," says Dr. Wise Young, director of the neurosurgical laboratory at New York University Medical School. "Drugs for use in the spinal-cord area can be extended to other diseases."

OVEREXCITED. The reason may be that, in all cases of injury to the central nervous system, the original trauma causes the death of cells in only one defined area. With a stroke, for example, the damage is caused by a blood clot or a bursting blood vessel--called an aneurysm--that shuts off the blood supply to an area of the brain. Affected cells die within a matter of minutes. But the damage doesn't stop there. As these original neurons, or brain cells, die, they unleash a chemical cascade that radiates outward like a nuclear explosion, eventually killing millions, if not billions, of neighboring nerve cells. "All of the injury that occurs with trauma is not immediate but expands over a day or two after," says Richard P. Bunge, director of the University of Miami's Project to Cure Paralysis. So far, science can do little to avoid the damage that occurs in the first few minutes after a stroke or injury. But drug companies are looking for remedies that would intervene in the delayed reaction and block much of the long-term damage to nerve cells.

The first step is to understand exactly what happens after the original trauma. Dr. Dennis W. Choi, head of the neurology department at Washington University in St. Louis, thinks that so-called excitotoxins play a major role in the damage. After a stroke or brain injury, he says, dying brain cells release massive amounts of a chemical called glutamate. Normally, glutamate is a key player in long-term memory and learning. But the brain functions under a very sensitive chemical balance, and too much glutamate is toxic. When the glutamate reaches weakened cell membranes, it causes "calcium channels" to open, allowing calcium to flood the cell. The effects of this flood are twofold: It "overexcites" the cell, stimulating the production of enzymes that ultimately lead to self-destruction. And the calcium triggers the release of more glutamate, so the chain reaction continues to spread to neighboring cells.

CHEMICAL COCKTAIL. One approach to stemming this destruction would be to use drugs that block the receptors, or docking sites, for glutamate on cell membranes. That would prevent the calcium channels from opening. Several large pharmaceutical companies, including Hoffmann-La Roche Inc. and Ciba-Geigy Corp., already have such drugs in early clinical trials for the treatment of stroke. Unfortunately, these drugs are relatives of the street drug called angel dust, which can cause some temporary--but serious--psychiatric problems.

By contrast, Fidia's GM-1, one of a class of naturally occurring compounds called gangliosides, seems to have few side effects. That's because, unlike the other drugs, it may block just those calcium channels involved in cell damage. Now, a few biotech companies, including Cambridge Neuroscience in Cambridge, Mass., and Neurex in Menlo Park, Calif., are working on even more precise ways to target the specific glutamate receptors that open the channels.

Still other companies are pinpointing different steps in this glutamate cascade. Neurotherapeutics, a San Diego startup, is trying to stop injured nerve cells from releasing glutamate in the first place. And Cortex Pharmaceuticals Inc., in Irvine, Calif., is working on inhibiting some of the damaging effects of calcium once it enters the cell. Calcium activates an enzyme called calpain that normally helps establish long-term memory. But when a flood of calcium is released into the cell, it acts as a switch, causing calpain to go haywire and destroy the cell from the inside out. Now, Cortex has developed a drug that--in animals--blocks this action.

According to Choi, the treatment of choice for stroke or brain injuries will probably include several of these drugs, a chemical cocktail of sorts. That's because glutamate isn't the only culprit in nerve-cell damage. In their swan song, dying cells also release large amounts of so-called free radicals. These are charged oxygen molecules that break down the fat particles that make up cell membranes. This makes the membranes leaky, again letting calcium flood the cell. Methylprednisolone, a generic drug that's now being used to treat spinal-cord patients, seems to infiltrate these cell membranes and help protect against free radicals. But because this drug is a steroid, it has some undesirable side effects--including suppression of the immune system.

BIGGER MIRACLES. In another approach, Upjohn Co. has discovered a whole new class of drugs, called lazaroids, that also lodge themselves in nerve-cell membranes and protect them from free radicals. One compound, tirilazade, has already been tested in people who have serious head injuries, and NYU's Young says it is "about a hundred times more potent than methylprednisolone and at the same time, it has no side effects." John M. McCall, executive director of discovery research at Upjohn, says lazaroids may also hold promise for strokes, and the company has started clinical trials to test them.

As researchers learn more about how to block the chemicals that cause the devastating damage from trauma and stroke, they are also getting hints about how to treat the long-term degeneration caused by Alzheimer's and Parkinson's disease. That's because the end result of trauma and neurodegenerative diseases is the same, says Young--"the loss of nerve cells." One theory about the cause of Alzheimer's, for example, is that glutamate and other excitotoxins may cause a slight, but chronic, overexcitement of the nerve cells, says Dr. Fred Gage, professor of neuroscience at the University of California in San Diego. The long-term effect could be to weaken these cells, making them vulnerable to other damage. In fact, says Upjohn's McCall, there is evidence that the brain of a person with Alzheimer's may be more sensitive than a normal person's to free radicals. For that reason, the company is trying to develop a lazaroid that could be tested against Alzheimer's--and even aging.

Researchers are eyeing even bigger miracles: They talk eventually of coaxing injured nerve cells to regenerate. In the meantime, there's plenty of work to do on trying to prevent central nervous system damage. "We've known about stroke for three centuries and still don't have a treatment," Choi says. Now, John Breeding is living proof that science is at long last making progress toward solving such problems.


Much of the damage to the central nervous system from a stroke or an injury to the brain or spinal cord is caused by toxic chemicals produced by the body itself. Now, researchers at several companies are testing new drugs that can block the effects of these chemicals--and thus prevent paralysis and other complications



After an injury, dying nerve cells release massive amounts of a brain chemical called glutamate. This sets off a chain reaction that overexcites neighboring nerve cells, eventually killing them. Some of these drugs, which are now in the experimental stage, would protect surrounding cells by blocking the receptors for glutamate on their membranes. Others would interfere with another step, the influx of calcium into the cells


UPJOHN After trauma, nerve-cell membranes also come under attack from so-called free radicals--charged oxygen molecules. The lazaroid drugs dissolve into the cell membranes and protect them from free-radical damage


FIDIA Gangliosides are proteins that are found in the membranes of nerve cells. They are believed to block calcium activity and may help stimulate nerve growth and repair. In recent experiments, injections of the proteins helped reduce paralysis caused by spinal-cord injuries


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