Compounds Prevent Alcohol's Disruption of Important Developmental Process

Two experimental compounds prevent one of the cellular events that is a likely contributor to fetal alcohol syndrome (FAS), according to a new study supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). A report of the study, by scientists at Harvard Medical School and the National Institute of Child Health and Human Development (NICHD), appears in the October 2002 issue of the Journal of Pharmacology and Experimental Therapeutics.*

"This important finding helps to strengthen our understanding of one way that alcohol damages the fetus and brings us a step closer to finding effective interventions against FAS," says NIAAA Acting Director Raynard Kington, M.D., Ph.D.

"This and other recent findings," adds senior author Michael E. Charness, M.D., Associate Professor of Neurology at Harvard Medical School and Chief of Neurology at the VA Boston Healthcare System, "provide valuable tools for identifying the target sites through which ethanol disrupts brain development and for designing drugs to prevent FAS."

Fetal cells destined to become the brain and nervous system attach to each other with the help of cell adhesion molecules, including one particular molecule called L1. The cells come together when L1 molecules on the surface of one cell and link up with L1 molecules on another. In recent laboratory studies Dr. Charness and his colleagues have shown that ethanol--the kind of alcohol in beverages--interferes with L1 adhesion molecules and hinders these crucial cell-to-cell attachments. They have also shown that octanol and other non-beverage alcohol molecules block ethanol's ability to disrupt L1 molecules and can prevent fetal damage from ethanol in mouse embryos.

In another recent study, Catherine Spong, M.D., Chief of the Pregnancy and Perinatology Branch at the National Institute of Child Health and Human Development, and her colleagues discovered that NAP and SAL, the active peptides from two brain proteins known to protect nerve cells against a variety of toxins, also protect mouse embryos from ethanol-induced fetal death and growth abnormalities.

In the current study, Dr. Charness and Harvard/VA colleagues Michael F. Wilkemeyer, M.D., Ph.D., and Carrie E. Menkari, B.S., teamed with Dr. Spong to determine if NAP and SAL protect against ethanol in the same way as octanol--by interfering with, or antagonizing, ethanol's disruption of L1-mediated cell adhesion.

The researchers conducted their experiments using cells designed to express L1 adhesion molecules and which are known to be very sensitive to ethanol. That is, they lose their ability to attach to each other and form clusters when mixed with ethanol.

However, extremely small concentrations of NAP or SAL were found to prevent this effect of ethanol-the cells clustered together even when mixed with lethal concentrations of ethanol. The researchers then demonstrated that NAP, which was significantly more potent than SAL, had the same effect on L1-expressing neural cells that were exposed to high concentrations of alcohol. NAP completely blocked ethanol inhibition of cell clustering.

The new finding further strengthens the case that ethanol causes birth defects by interfering with L1-mediated cell adhesion.

"We now know that these molecules can prevent ethanol-induced fetal damage in mice," says Dr. Spong. "Studying them may provide even more effective methods for preventing the injury that alcohol causes in the developing fetus."

The leading preventable cause of mental retardation in the United States, FAS affects about 1 in 1,000 U.S. infants and about 6 percent of children born to alcoholic women.

For interviews with Dr. Charness, please contact 617/ 325-2815 or mcharness@hms.harvard.edu. For interviews with Dr. Spong, please telephone Bob Bock or Marianne Glass Duffy at 301/496-5133. For interviews with Dr. Kington, please telephone Ann Bradley at 301/443-0595 or 301/443-3860. Additional information about FAS research is available at http://www.niaaa.nih.gov. NICHD publications, as well as information about the Institute, are available from the NICHD web site, http://www.nichd.nih.gov, or from the NICHD Information Resource Center, 1-800-370-2943; e-mail NICHDInformationResourceCenter@mail.nih.gov.

NIAAA and NICHD are components of the National Institutes of Health, U.S. Department of Health and Human Services. NIAAA conducts and supports research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.

* M. F. Wilkemeyer, C. E. Menkari, C. Y. Spong, and M. E. Charness. Peptide Antagonists of Ethanol Inhibition of L1-Mediated Cell-Cell Adhesion. J Pharmacol Exp Ther 303(1):110-116, 2002. Available online at: http://jpet.aspetjournals.org/
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