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Neuronal rescue by refrigeration: drug tests yield a chilling surprise.

Neuronal Rescue by Refrigeration

An experimental drug that scientists had hoped might usher in the first generation of highly specific, nerve-protecting agents appears less promising with the publication of a new series of experiments, but has generated excitement about an even cooler approach.

Initial studies performed on tissue cultures and in animals had hinted that the drug, called MK-801, might dramatically reduce nerve death in the brains of people after they had suffered a heart attack or stroke (SN: 11/4/89, p.292). But recent findings in animals suggest MK-801's usefulness comes not so much from any specific neuroprotective actions as from a simple, drug-induced drop in body temperature. Since the potent drug seems to carry some risks of its own, and simpler ways exist to drop body temperature, the surprising finding has dampened some researchers' hopes for the compound.

Scientists say additional research may reveal specific conditions for which the drug has value. More immediately, however, the findings have spawned renewed interest in discovering other, less risky ways of chilling the body as a strategy for minimizing nerve death following an interruption in the brain's blood supply.

Heart attacks and strokes deprive the brain of oxygenated blood. Not only is brain tissue exquisitely sensitive to such a loss, but it suffers additional damage from the sudden influx of oxygen in the minutes following restoration of blood flow. Although the mechanisms behind both of these neuron-destroying events remain poorly understood, research suggests that much of the damage results from a series of biochemical reactions that start with the binding of so-called excitatory amino acids, such as glutamate, to nerve-cell docking sites called NMDA receptors. MK-801, a close chemical relative of the psychoactive street drug PCP, belongs to a class of drugs called NMDA antagonists, which can disrupt NMDA receptor function.

Developed by Merck Sharp & Dohme Research Laboratories in West Point, Pa., MK-801 was about to go into clinical trials for stroke patients last year when John W. Olney and his colleagues at the Washington University School of Medicine in St. Louis reported evidence that the drug itself might damage neurons in the cerebral cortex when given to rats in relatively low doses. Although the risk to humans remained unclear, the findings prompted an indefinite postponement of human testing.

Even before those findings, however, various experiments in gerbils and rats had provided disturbingly differing results as to whether the compound actually did or did not enhance neuronal survival when large parts of the animals' brains were deprived of oxygen for approximately five minutes -- a condition mimicking a heart attack. In some of these experiments the drug appeared to provide remarkable protection; other experiments showed no benefit at all.

Alastair Buchan and William A. Pulsinelli of the Cornell University Medical College in New York City now appear to have solved the riddle behind these inconsistent results. In gerbils, they simulated a heart attack's effect on the brain by temporarily blocking the animals' carotid arteries and found that MK-801's effectiveness varied depending on body temperature.

When the researchers allowed the drug to lower the test animals' temperatures by about 4[degrees]C, as it tends to do for several hours after administration, brain-neuron damage was indeed reduced. But animals not receiving the drug did equally well if the scientists chilled them to the same lowered temperature by putting them in a refrigerated room soon after restoring blood flow. Significantly, test gerbils kept at their normal body temperatures with heating lamps showed substantial loss of neurons even if they got the drug.

By reviewing the records of previous experiments in rats and gerbils, Buchan and Pulsinelli found that other researchers had not controlled for such temperature effects. Some researchers, it appears, maintained their test animals' normal body temperatures in warm laboratories while others seem to have allowed their animals to cool. Indeed, not realizing that temperature was a relevant variable, most researchers hadn't paid any attention to temperature at all, they say.

Based on their experiments, Buchan and Pulsinelli conclude in the January JOURNAL OF NEUROSCIENCE that neural protection by MK-801 "is related largely to the prolonged hypothermia caused by this drug." In light of the ongoing disagreement over how much neural damage the drug may cause -- a debate reignited in an exchange of comments in the Jan. 12 SCIENCE -- the finding leaves MK-801's fate uncertain, researchers say.

"It obviously raises the specter of a very specific problem" with the studies performed so far, comments Dennis Choi, a neuroscientist at Stanford University who has tested the drug on mouse tissue cultures.

Some maintain the drug may still find a place in the physician's armamentarium. Experiments by Olney's group at Washington University, for example, indicate that in newborn rats--which respond to a lack of oxygen somewhat differently than do gerbils -- MK-801 in conjunction with lowered body temperatures proves more beneficial than lowered temperatures alone. And Choi notes that the drug still shows some promise for the more localized neural asphyxiation seen in strokes, suggesting that stroke victims may someday gain some benefits from the drug even if heart attack patients don't. But in the long run, researchers say, only clinical trials will settle the issue of MK-801's true value.

Whatever the future of MK-801, Buchan and Pulsinelli's findings provide new incentive for researchers to investigate the value of inducing lowered body temperatures in patients who have just suffered a heart attack or stroke. For years, surgeons performing operations that may temporarily limit oxygen supplies to the brain have reduced the risk of surgery-related brain damage by chilling patients in advance--generally by placing them in a cooled room and by infusing them with chilled intravenous fluids. And reports of children who have remained submerged in near-freezing water for prolonged periods without apparent brain damage indicate that low brain temperatures during oxygen deprivation can also protect brain neurons. Their new work, Buchan and Pulsinelli say, now clearly indicates that hypothermia of even a few degrees, soon after a loss of oxygen, can have an equally impressive neuroprotective effect.

Given those findings, Pulsinelli and others maintain that a degree of refrigeration might prove useful as an emergency therapy in victims of heart attacks or strokes. But for now, physicians note, hospitals are not prepared to induce hypothermia on an emergency basis.

"The question is, can you do it quickly enough?" says Buchan, now at the University Hospital in London, Ontario. He and others wonder whether any kind of drug can safely lower core temperatures with sufficient rapidity in human beings, whose body masses are substantially greater than those of any animals currently under such investigation.

Along with the challenge of dropping body temperatures quickly, researchers have yet to determine just how cold is cold enough. European researchers, who have reported successfully preventing brain damage in oxygen-deprived newborns by dunking them in chilled water for up to 15 minutes, have noted that longer exposures to temperatures below 29[degrees]C may prove detrimental. Similarly, while some early attempts to chill heart attack victims to 25[degrees]C effectively rescued brain neurons, Buchan says the treatment wreaked metabolic havoc elsewhere in the body. Among other things, the very low temperatures triggered coagulation problems and cardiac arrhythmias.

Recently, researchers have suggested cooling such patients to a more moderate 33[degrees]C. But ideally, Buchan says, physicians would like to cool the brain to these temperatures without having to chill the rest of the body -- thus avoiding the various metabolic side-effects of hypothermia, including the adrenalin release that comes with intense shivering.

Buchan says one approach would be to inject cold saline directly into some of the cavities, or sinuses, in the brain. But so far, he says, no one has tested the approach in a clinical trial.
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Author:Weiss, Rick
Publication:Science News
Date:Mar 10, 1990
Words:1287
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