Researchers Identify Alcohol Antagonists In Neural Cells

Harvard Medical School and Veterans Administration researchers report in today's Proceedings of the National Academy of Sciences that certain long-chain alcohols can block harmful effects of short-chain alcohols including ethanol (beverage alcohol) on nerve cell growth and development. "The findings may lead eventually to medications that reduce the damaging effects of alcohol in both fetal development and in adults," said Michael Charness, M.D., Associate Professor in the Department of Neurology, Harvard Medical School, and Chief of Neurology, VA Boston Healthcare System.

Supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Medical Research Service, Department of Veterans Affairs, the study builds on earlier work by Dr. Charness and his colleagues that, in 1996, showed that ethanol disrupts cell adhesion mediated by the L1 cell adhesion molecule. This finding was striking because of the similarity in brain lesions between children with mutations in the gene for L1 and children with fetal alcohol syndrome. Molecular tags that protrude from nerve cell membranes and stick to similar molecules on adjacent cells, cell adhesion molecules such as L1 influence neuronal migration and the extension and bundling of neuronal processes, functions that are essential for normal human nervous system development. L1 also is believed to play a role in long-term synaptic changes that may influence learning and memory.

In today's study, Harvard Medical School Instructor of Neurology Michael Wilkemeyer, Ph.D., and Dr. Charness examined the effects of alcohols of various shapes and sizes on nerve cell adhesion. They found that relatively small alcohols (including ethanol) with fewer than five carbons inhibit cell adhesion with increasing potency but that the effect abruptly ceases between four-carbon butanol and five-carbon pentanol. "Butanol interferes with L1 but pentanol and larger alcohols have no effect. That leads us to believe that there must be some kind of pocket into which only the small alcohols fit," said Dr. Charness.

Shape of the alcohol molecule may be even more important than size in regulating the interaction, the researchers claim. By adjusting the shape of butanol, they rendered that molecule inactive (i.e., with no effect on cell-cell adhesion), suggesting a specific lock-and-key interaction between the alcohol molecule and its receptor. "Our analysis indicates that the alcohol target discriminates among alcohols of equivalent molecular volume and is exquisitely sensitive to molecular shape," Dr. Wilkemeyer said.

In exploring potential antagonists of this lock-and-key interaction, the research team tried the longer chain alcohols identified as inactive on cell-cell adhesion. When they introduced long-chain alcohols such as pentanol and octanol, nerve cells again clumped together in a complete reversal of ethanol's antiadhesive effects. Octanol also completely reversed the antiadhesive effects of ethanol on nerve cells in culture that were exposed to growth factor BMP-7.

"This fascinating work brings us closer to understanding and possibly preventing at least some neurotoxic effects of alcohol," said NIAAA director Enoch Gordis, M.D. "The field will watch closely to see whether what works in the laboratory also works in animal models."

The leading preventable cause of mental retardation in the United States, FAS affects about one in 1,000 U.S. infants and about 6 percent of the offspring of alcoholic mothers. Children with FAS exhibit growth retardation, malformations of the brain, face, and heart, and behavioral disorders while children with less severe fetal alcohol effects exhibit neurobehavioral deficits. In addition, alcohol abuse can lead to neurological disorders in adults, disrupting memory and learning. NIAAA supports research into several mechanisms whereby alcohol may damage the developing and the adult brain. Today's report describes a specific, nonenzymatic antagonist of ethanol in neural cells.