Mouse study identifies protective mechanism against alcohol-induced embryo toxicity

June 09, 2003

Researchers have identified a mechanism by which the eight amino acid peptide NAP, an active fragment of a neuroprotective brain protein, protects against alcohol-induced embryo toxicity and growth retardation in mice. Their findings bring alcohol researchers a critical step closer to developing pharmacologic agents to prevent alcohol-induced fetal damage. The study, funded by the National Institutes of Health's National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Child Health and Human Development (NICHD), and the Medical Research Service, Department of Veterans Affairs, appears in the current issue of the Proceedings of the National Academy of Sciences.*

The researchers produced NAP derivatives with specific substitutions and screened the compounds in cultured rat neurons for their protection against cell toxins and in whole mouse embryos for their protection against alcohol. By manipulating NAP's structure and thereby altering its activity, the researchers were able to examine the ability of the different NAP derivatives to block alcohol inhibition of the L1 cell adhesion molecule. Their results indicate that NAP protects mouse embryos from alcohol toxicity by blocking alcohol effects on L1 rather than by its broad neuroprotective actions.

"This elegant study demonstrates that the protective effect of NAP against alcohol damage differs from that of NAP against neurotoxins, said Ting-Kai Li, M.D., Director, National Institute on Alcohol Abuse and Alcoholism. "Ethanol inhibition of L1 is now strongly implicated in the pathogenesis of fetal alcohol damage and a foremost target of medication development."

Michael Charness, M.D., of the Veterans Administration Boston Healthcare System and Department of Neurology, Harvard Medical School, headed up the study, with colleagues from the NICHD and the University of North Carolina Bowles Center for Alcohol Studies.

NAP, technically known as NAPVSIPQ, is known to be protective in minute concentrations against a wide array of neural insults and recently was shown to prevent alcohol-induced fetal wastage and growth deficits in mice. In September 2002, Dr. Charness with other colleagues reported that NAP also blocks alcohol's inhibitory effects on cell-cell aggregation (the clustering of fetal cells destined to become the brain and nervous system) as mediated by the cell adhesion molecule known as L1. Whether NAP's broader neuroprotective action or its specific effects on cell adhesion were responsible for preventing fetal damage remained to be determined.

The leading preventable cause of mental retardation in the United States, fetal alcohol syndrome affects about 1 in 1,000 U.S. infants and about 6 percent of children born to alcoholic women. Fetal alcohol syndrome imposes lifetime economic costs estimated at $1.8 million per child in health care and indirect costs such as lost productivity.
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For an interview with Dr. Charness, telephone 617/325-2815 or email mcharness@hms.harvard.edu. For interviews with Dr. Li or other NIAAA staff, please telephone the NIAAA Press Office (301-443-0595 or -3860). Additional information on fetal alcohol syndrome and other subjects of NIAAA research is available at www.niaaa.nih.gov.

The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to science, practitioner, policy making, and general audiences.

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*Michael F. Wilkenmeyer, Shao-yu Chen, Carrie E. Menkari, Douglas E. Brenneman, Kathleen K. Sulik, and Michael E. Charness. Differential Effects of Ethanol Antagonism and Neuroprotection in NAPVSIPQ Prevention of Ethanol-Induced Developmental Toxicity. Available in the PNAS Online Early Edition the week of June 9-13, 2003 at www.pnas.org/cgi/doi/10.1073/pnas.1331636100.

NIH/National Institute on Alcohol Abuse and Alcoholism

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