Mouse Study Identifies Protective Mechanism Against Alcohol-Induced Embryo Toxicity
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
Healths 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 NAPs 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
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 alcohols 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 NAPs 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.
For an interview with Dr. Charness, telephone (617) 325-2815 or
email firstname.lastname@example.org. For interviews
with Dr. Li or other NIAAA staff, please telephone the NIAAA Press
Office at (301) 443-0595 or (301) 443-3860. 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.
*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.