Prevention of alcohol-induced developmental delays and learning abnormalities in a model of fetal alcohol syndrome.
OBJECTIVE
Prenatal alcohol exposure results in fetal death and neurobehavioral complications including learning impairment. Previously synthetic peptides derived from activity-dependent neurotrophic factor have been shown to prevent aspects of alcohol-induced damage in pregnancy. The objective of this work was to evaluate whether activity-dependent neurotrophic factor-12 could prevent alcohol-induced damage in a model of fetal alcohol syndrome.


METHODS
Using a well-characterized model, C57Bl6/J mice on gestational day 8 were treated with placebo, alcohol (30% volume/volume alcohol 0.03 mL/kg), alcohol plus activity-dependent neurotrophic factor-12 30 minutes prior to alcohol, or activity-dependent neurotrophic factor-12 alone. Fetal death was assessed on gestational day 18 (25 litters were evaluated: alcohol, n = 5; placebo, n = 9; alcohol plus activity-dependent neurotrophic factor-12, n = 11). Neonatal behavior tests were performed on postnatal days 1 through 21 with the offspring of 12 dams (alcohol, n = 16; placebo, n = 46; alcohol plus activity-dependent neurotrophic factor-12, n = 23; and activity-dependent neurotrophic factor-12, n = 35). Adult males were tested in the Morris water maze for learning assessment and with the hole punch activity test for exploratory activity. Statistical analysis included Kruskal-Wallis and analysis of variance.


RESULTS
Fetal death was greater in alcohol (67% +/- 13%) vs placebo (8.4% +/- 3%, P < .001). Pretreatment with activity-dependent neurotrophic factor-12 prevented the alcohol-induced fetal death (2.2% +/- 8.1%) with levels similar to control (P = .12). Alcohol exposure caused a delay in achieving developmental milestones, with alcohol achieving milestones later than all other groups (all P < .001). Pretreatment with activity-dependent neurotrophic factor-12 prevented the alcohol-induced milestone delays. In the Morris water maze, the placebo learned, decreasing their latency to find the hidden platform over 70% (P < .01). Alcohol plus activity-dependent neurotrophic factor-12 also significantly learned, with a learning curve not different from placebo (all P > .5) and significantly better than alcohol on days 4, 6, and 7 (all P < .05). Alcohol exposure resulted in significantly less time in hole punch activity (P < .02) than control. Activity-dependent neurotrophic factor-12 pretreatment prevented the alcohol-induced decline, with levels the same as control (P = .1).


CONCLUSIONS
The novel peptide activity-dependent neurotrophic factor-12 prevents alcohol-induced fetal death and developmental and learning abnormalities in a model of fetal alcohol syndrome. This demonstrates that a single treatment with a peptide is efficacious and may be of value in the prevention of alcohol-induced damage.
Endres
M
M
Unit on Perinatal and Developmental Neurobiology, National Insitute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-0925, USA.
Toso
L
L
Roberson
R
R
Park
J
J
Abebe
D
D
Poggi
S
S
Spong
C Y
CY
D000818:Animals; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D005313:Fetal Death / Q000517:prevention & control; D005317:Fetal Growth Retardation / Q000517:prevention & control; D007858:Learning / Q000187:drug effects; D007859:Learning Disabilities / Q000139:chemically induced / Q000517:prevention & control*; D018782:Maze Learning; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000627:therapeutic use*; D011247:Pregnancy
D009419:Nerve Tissue Proteins; D000431:Ethanol