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Weekly Research Spotlight
Compiled by Michael
Ybarra
Prevention of alcohol-induced
developmental delays and learning abnormalities in a
model of fetal alcohol syndrome
Researchers at the National
Institute of Child Health and Human Development have
found a way to minimize the deleterious affects of
prenatal alcohol exposure on developmental and learning
abnormalities in a model of fetal alcohol
syndrome. The objective of their work, published
recently in the American Journal of Obstetrics and
Gynecology, was to evaluate whether activity-dependent
neurotrophic factor-12 could prevent alcohol-induced
damage in a well-studied mouse model. The mice
were given alcohol plus activity-dependent neurotrophic
factor-12 on day 8 of gestation and their offspring were
compared to those of mothers given alcohol alone.
Fetal death was decreased when mothers were pretreated
with activity-dependent neurotrophic factor-12.
Developmental milestones were also measured, and the
pretreated mother’s gave birth to offspring that were no
different from placebo, and significantly better than
alcohol alone at mastering a Morris water maze and a
hole punch activity. The researchers concluded
that “activity-dependent neurotrophic factor-12 prevents
alcohol-induced fetal death and developmental learning
abnormalities in a model of FAS.”
Mitochondrially targeted vitamin
E and vitamin E mitigate ethanol-mediated effects on
cerebellar granule cell antioxidant defense system
Animal studies have revealed
that prenatal exposure to alcohol can cause
mitochondrial dysfunction, intracellular oxidant
accumulation, and suppression of endogenous antioxidants
defense systems. Marieta Heaton’s group at the
McKnight Brain Institute of the University of Florida is
actively researching the cellular mechanisms
that underlie alcohol-induced damage and the
protective mechanisms of potential therapeutics against
prenatal alcohol exposure. Previous studies from
this group show that, in vivo, natural vitamin E reduces
neuronal death in the cerebellum of alcohol-exposed
animals. In vitro studies show that natural
vitamin E prevents apoptosis and necrosis in
alcohol-exposed cerebellar granule cells. The most
recent study by Kendra Siler-Marsiglio et al., shows
that vitamin E chemically-engineered to target the
mitochondria inhibits intracellular oxidant
accumulation, mitigates alcohol-mediated
suppression of antioxidant systems, and promotes
cell survival at much lower concentrations than natural
vitamin E. This modified vitamin E, targets the
mitochondria and provides significant neuroprotection
against alcohol concentrations as high as 1600
mg/dl. Bioavailability studies of
orally-administered mitochondrially-targeted vitamin E
show that it can cross the blood-placenta barrier of
pregnant dams to reach the fetus and the blood-brain
barrier; both are essential for a FAS therapy.
Mitochondrially-targeted vitamin E shows promise as a
future therapeutic strategy against damage and death
cause by prenatal alcohol exposure. Brain Res.
2005 Jul 15; [Epub ahead of print]
Alcohol Inhibits Survival
Signals in the Cerebellum of an FAS Animal Model
Alcohol inhibits
insulin-stimulated survival signals causing cerebellar
hypoplasia in the developing brain, according to
researchers at the Rhode Island Hospital. Using a
rat model of FAS, this study found a decreased
expression of the insulin gene in the cerebella of
exposed rats. Alcohol exposure also caused a
decrease in the amount of insulin, insulin-like growth
factor receptor tyrosine kinase, glucose transport
molecules, and steady-state levels of ATP in the cells
of the cerebellum. These results suggest
cerebellar hypoplasia resulting from prenatal alcohol
exposure is caused by a deficient energy supply.
Cell Mol Life Sci. 2005
May;62(10):1131-45.
Prenatal Alcohol Exposure Alters
Maternal and Fetal Endocrine Systems
Studies done at the
University of British Columbia may have uncovered the
link between prenatal alcohol exposure and some of the
long-term symptoms of FASD. Alcohol consumption
affects both the maternal and fetal endocrine systems,
altering the interaction between maternal-fetal
hormones. Additionally, exposure to alcohol can
cause reprogramming of the
hypothalamic-pituitary-adrenal (HPA) axis in the fetus
so that HPA tone is increased throughout life.
Increasing HPA tone causes excess secretion of
glucocorticoids. This in turn leads to altered
behavioral and physiologic responses.
Glucocorticoid secretion also causes suppression of the
immune system which will increase the individual’s
vulnerability to disease later in life. The
endocrine affects of alcohol exposure may explain the
behavioral, cognitive, and immune deficits seen in
patients with FASD. Exp Biol Med (Maywood).
2005 Jun;230(6):376-88.
Ercc61 May Play a Role in the
Tertogenic Action of Alcohol
Researchers at Peking
University’s School of Public Health have discovered a
mouse gene, Ercc61 that may account for the mutagenic
affects of prenatal alcohol exposure. Ercc61 is
normally expressed in the neural tube and heart of a
10.5-day old mouse embryo. Expression of Ercc61
was significantly down-regulated after in-utero alcohol
exposure on days 6-10. On day 15, expression of
Ercc61 in the brain and heart (the two organs most
affected by Fetal Alcohol Syndrome), were markedly
decreased following alcohol exposure. This result
suggests Ercc61 might play a role in the mutagenic
affects of alcohol consumption during pregnancy.
Toxicol Let. 2005 Jul 4;157(3):233-9
Research Investigating
Effects of Alcohol and Developing Brain
Cells
Even brief exposures to small amounts of
alcohol may kill brain cells in a developing fetus. A
study carried out by John Olney, M.D., at the Washington
School of Medicine in St. Louis showed that just two
drinks consumed during pregnancy may be enough to kill
some developing brain cells, leading to permanent brain
damage. Nerve cells will die if they fail to make
synaptic connections in time. Drinking alcohol can
interfere with the formation of these connections. Based
on the animal studies carried out by Dr. Olney, it does
not take much alcohol to have this effect. In unborn
mice, the concentration of alcohol needed to kill
developing brain cells was 0.07 percent. In most women,
two cocktails is enough to elevate blood alcohol levels
to this amount. Dr. Olney's advice is for pregnant women
to completely avoid alcohol until further research can
better explain the sensitivity of developing brain cells
to alcohol.
Addiction Biology 2004
Jun;9(2):137-49
Nerve Damage Caused by
Prenatal Alcohol Exposure
It is well known
that prenatal alcohol exposure can cause damage to the
central nervous system. But a study conducted by the
National Institute of Child Health and Human Development
at the National Institutes of Health showed that babies
can suffer nerve damage in the arms and legs, too.
Researchers compared 17 full-term newborns whose mothers
drank heavily while pregnant with 13 newborns whose
mothers did not drink. "Heavy drinking" was defined as
having four or more standard drinks a day—a standard
drink being a can of beer, one glass of wine or one
mixed drink.
Babies exposed to alcohol showed nerve damage in
their arms and legs at both one month and one year of
age, suggesting developing nerve cells were permanently
damaged. The researchers will continue to study these
children to find out the long-term effects of alcohol
exposure on nerve function, motor skills and touch
sensation.
Links:
From the
CDC: New! FAS Guidelines for Referral and
Diagnosis
NIH News: New Study Finds Babies Born To Mothers Who
Drink Alcohol Heavily May Suffer Permanent Nerve
Damage |