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Damage Mechanism

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Embargoed for release until 2 P.M. ET, Thursday, Feb. 10, 2000

Researchers Identify Damage Mechanism in Fetal Alcohol Syndrome

St. Louis, Feb. 11, 2000 – For years, physicians and scientists have known that alcohol has detrimental effects on the human fetus. A new study from investigators in Berlin, Tokyo and St. Louis identifies how the damage associated with fetal alcohol syndrome might occur.

A paper in today’s issue of Science reports that a single exposure to high levels of ethanol (the alcohol in beer, wine and spirits) can kill nerve cells in the developing brain. The researchers found that the rat brain is sensitive to this toxic effect during a brain development stage that corresponds to the brain growth spurt in humans. Called synaptogenesis because it is the time when brain cells form most of their interconnections, the brain growth spurt lasts from about the sixth month of pregnancy to a child’s second birthday. In rats, synaptogenesis occurs after a pup is born.

The scientists intoxicated infant rats by giving them ethanol for periods of four or more hours. This maintained the alcohol level at about 0.2 (200 mg ethanol per deciliter of blood) — about twice the level that defines legal intoxication in humans. This one-time exposure caused brain cells to commit suicide by a process called apoptosis or programmed cell death. The rate of cell death exceeded the spontaneous rate of cell death by almost 30 times in some parts of the brain — spontaneous cell death removes surplus cells from the developing brain.

The investigators say finding that cells can die after a single episode of alcohol intoxication means it would be prudent for expectant mothers to avoid alcohol intoxication during pregnancy.

"For many years, scientists studying fetal alcohol syndrome have tended to expose rats to alcohol for longer periods of time rather than studying the damage more transient exposure might cause," said John W. Olney, M.D., the study’s senior investigator and the John P. Feighner Professor of Neuropsychopharmacology at Washington University School of Medicine in St. Louis. "We exposed the infant rats just once, keeping them intoxicated for a period of just a few hours, and we found that was sufficient to trigger considerable damage in the developing brain."

The paper’s lead author, Chrysanthy Ikonomidou, M.D., associate professor of pediatric neurology at Humboldt University in Berlin, previously was a postdoctoral fellow in Olney’s laboratory, as was another author, Masahiko J. Ishimaru, M.D., Ph.D., who now is based at the Tokyo Medical and Dental University. The three collaborated with other colleagues at their institutions to conduct the study. The researchers found no evidence that exposure to small amounts of alcohol had cumulative effects on the developing brain. Rather, substantial intoxication was required before significant damage occurred. While translating effects from rats to humans is difficult, Olney believes it is unlikely that a single glass of wine would cause the damage observed in these experiments, even if expectant mothers consumed a very small amount of alcohol every day. Because it is not entirely clear how rats and humans compare in sensitivity to alcohol, however, the investigators believe it is best to avoid alcoholic drinks completely during pregnancy.

The investigators also studied the mechanism of this alcohol-induced brain cell death. It is known that alcohol can interfere with certain transmitter systems in the brain. The systems use chemical molecules, such as glutamate and GABA, to activate nerve cell receptors and transmit messages from one cell to another. In research reported last year in Science, Olney and colleagues found that drugs called NMDA antagonists, which interfere with glutamate transmission in the same way that alcohol does, have a similar cell-killing effect in the infant rat brain when given as a single high dose. In the current study, the investigators found that drugs that excessively activate GABA receptors, as alcohol does, also can kill nerve cells in the infant rat brain.

"Our evidence documents that alcohol acts by two mechanisms — blockade of glutamate transmission and excessive stimulation of GABA transmission. By combining these two mechanisms, it produces a compound pattern of damage that is greater than either mechanism would produce by itself," Olney said.

Much of the significance of the findings comes from the fact that alcohol is so widely used throughout the world. "However, it must be recognized that numerous other drugs act either by blocking glutamate receptors or activating GABA receptors, and many of these drugs are drugs of abuse and/or are used in pediatric medicine as sedatives, anticonvulsants or anesthetics," Olney said. "In fact, the only drugs available for anesthetizing human infants act either by blocking NMDA receptors or activating GABA receptors."

Drugs of abuse that block NMDA glutamate receptors include phencyclidine (PCP or "angel dust"), ketamine (special "K") and nitrous oxide (laughing gas). Both ketamine and nitrous oxide are used frequently in pediatric anesthesia. GABA receptor activators that are frequently abused and/or used in pediatric anesthesia include benzodiazepines, barbiturates, isoflurane and propofol.

"In light of this new evidence, it obviously is prudent for expectant mothers to avoid any of these drugs," Olney said. "It also will be important to carefully reevaluate how these drugs are used in pediatric medicine with an aim toward developing guidelines that ensure an adequate margin of safety."

The death of neurons by apoptosis occurs naturally. It enables the brain to get rid of unhealthy cells or cells that are not needed for normal brain development. "But what we saw was cell death at many times the normal rate," Ikonomidou explained. "And alcohol and these other drugs don’t just cause cells that are going to die anyway to die more quickly. They cause cells that never would have died under normal circumstances to commit suicide. And millions are involved."

These mechanisms may contribute to the wide variety of neurological and psychiatric symptoms seen in individuals with fetal alcohol syndrome. Symptoms range from hyperactivity and learning disabilities in childhood to depression or severe psychosis in adulthood. Olney believes the variety of symptoms may be explained by the timing of alcohol exposure. In the rat, he found that different populations of neurons were vulnerable at different times during synaptogenesis.

"So if the toxic event occurs early in synaptogenesis, it will delete groups of neurons that develop sensitivity early. If it occurs later, those neurons will be spared, but other groups will be deleted," Olney explained.

Olney and Ikonomidou will continue to investigate the impact of alcohol and drug exposure on the developing brain by studying rats as the animals mature. They will determine which specific brain damage patterns are associated with specific behavioral and neurological problems that develop later in life.

"Many psychiatric and neurological disorders are thought to originate from events that occur during development," Olney explained. "This model will allow us to establish some correlations between damage to specific cell populations during development and subsequent neuropsychiatric problems."

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This research was supported by grants from the National Institute of Mental Health, the National Institute on Aging, the National Institute on Drug Abuse, the National Eye Institute, the National Alliance for Research on Schizophrenia and Depression, the Deutsche Forschungsgemeinschaft (DFG) and Humboldt University.

C. Ikonomidou, et al. Ethanol-Induced Apoptotic Neurodegeneration and the Fetal Alcohol Syndrome. Science, vol. 287 p1056-1060, Feb. 11, 2000.

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