Neuronal rescue by refrigeration: drug tests yield a chilling surprise

Science News, March 10, 1990 by Rick Weiss

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.