A paper in the Jan. 1 issue of Science reports that a class of drugs used to anesthetize children and sometimes abused by pregnant women can cause death of nerve cells in the developing brain. The researchers found that the rat brain is sensitive to this toxic effect during a specific stage in development that corresponds to the brain growth spurt in humans, which lasts from about the sixth month of pregnancy to a child's second birthday.
The compounds, which belong to a class called NMDA antagonists, include phencyclidine (PCP or "angel dust"), ketamine ("special K") and nitrous oxide (laughing gas), all of which are drugs of abuse. In addition, ketamine and nitrous oxide are used commonly as anesthetics in pediatric medicine. Exposing young rats to these agents for a period of four hours or more caused nerve cells in the brain to die by a process called apoptosis, or programmed cell death, in which cells commit suicide. The rate of cell death triggered by these compounds exceeded the spontaneous rate of cell death by almost 30 times in some brain regions.
"The death of nerve cells by apoptosis is a natural process that occurs in the normal brain during development," explained lead author Chrysanthy Ikonomidou, M.D., associate professor of pediatric neurology at Humboldt University in Berlin. "It is the way the brain gets rid of unhealthy cells or cells that are not needed for normal brain development. But what we saw in these experiments was cell death at many times the normal rate."
Not only is the rate of cell death higher, the brain cells that die are neurons that would not have died otherwise, she said.
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Ikonomidou made the discovery in collaboration with co-author John W. Olney, M.D., professor of psychiatry and of neuropathology at the School of Medicine. For many years, Olney has been studying glutamate, an important transmitter in the brain, and NMDA antagonists, drugs that block NMDA glutamate receptors on brain cells. He has developed evidence implicating this glutamate receptor system in various adult disease processes ranging from stroke to Alzheimer's disease to schizophrenia. The new findings reported Jan. 1 in Science implicate glutamate and NMDA receptors in disease processes affecting the developing nervous system.
The toxic action occurs during the period of synaptogenesis, when immature nerve cells are forming synaptic connections with one another. Through NMDA receptors located at these synaptic connections, glutamate can help promote the survival and healthy development of neurons. NMDA antagonists that block glutamate's action at these receptors interfere with this survival mechanism.
"Our evidence indicates that during the stage of synaptogenesis, neurons require a certain level of stimulation through NMDA receptors. If they don't get that stimulation, the neuron interprets that as a signal to commit suicide," Olney said.
This toxic mechanism can delete large numbers of neurons from many different regions of the developing brain because many neurons depend on stimulation of their NMDA receptors for survival. In addition, the mechanism may contribute to a wide variety of neurological or psychiatric symptoms.
"The symptoms can vary widely," Olney explained, "because the type of symptoms depends on the type of neurons that are deleted, and different types of neurons become sensitive to this toxic mechanism at different times within the synaptogenesis period. That means if the toxic event occurs early in synaptogenesis, it will delete groups of neurons that develop sensitivity early. If it happens later, those neurons will be spared, but other groups will be deleted."
Olney and Ikonomidou believe the full significance of these findings is not yet clear, and both plan further investigation of the mechanism and the drugs that contribute to it.
Nitrous oxide, for example, has been used for over a century as an anesthetic in dentistry and medicine, but until recently its mechanism of action was unknown. Earlier this year, another researcher working in Olney's laboratory, Vesna Jevtovic-Todorovic, M.D., assistant professor of anesthesiology, discovered and reported in Nature Medicine that nitrous oxide is an NMDA antagonist.
"Our present findings show that several anesthetics and drugs of abuse can trigger the cell suicide process, but other similar drugs still must be tested," Olney said. "For example, alcohol is abused by many people, including pregnant women, and it has the properties of an NMDA antagonist. So we currently are investigating whether it can trigger neuronal suicide in the developing brain. In addition, certain anesthetic agents such as ketamine and nitrous oxide are sometimes used in combination with one another. We want to explore the possibility that the risk of brain damage may be increased by using these drugs in combination."
