Prevention of fetal demise and growth restriction in a mouse model of fetal alcohol syndrome.
Two peptides [NAPVSIPQ (NAP) and SALLRSIPA (ADNF-9)], that are associated with novel glial proteins regulated by vasoactive intestinal peptide, are shown now to provide protective intervention in a model of fetal alcohol syndrome. Fetal demise and growth restrictions were produced after intraperitoneal injection of ethanol to pregnant mice during midgestation (E8). Death and growth abnormalities elicited by alcohol treatment during development are believed to be associated, in part, with severe oxidative damage. NAP and ADNF-9 have been shown to exhibit antioxidative and antiapoptotic actions in vitro. Pretreatment with an equimolar combination of the peptides prevented the alcohol-induced fetal death and growth abnormalities. Pretreatment with NAP alone resulted in a significant decrease in alcohol-associated fetal death; whereas ADNF-9 alone had no detectable effect on fetal survival after alcohol exposure, indicating a pharmacological distinction between the peptides. Biochemical assessment of the fetuses indicated that the combination peptide treatment prevented the alcohol-induced decreases in reduced glutathione. Peptide efficacy was evident with either 30-min pretreatment or with 1-h post-alcohol administration. Bioavailability studies with [(3)H]NAPVSIPQ indicated that 39% of the total radioactivity comigrated with intact peptide in the fetus 60 min after administration. These studies demonstrate that fetal death and growth restriction associated with prenatal alcohol exposure were prevented by combinatorial peptide treatment and suggest that this therapeutic strategy be explored in other models/diseases associated with oxidative stress.
Spong
C Y
CY
Section on Developmental and Molecular Pharmacology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA. spongc@exchange.nih.gov
Abebe
D T
DT
Gozes
I
I
Brenneman
D E
DE
Hill
J M
JM
D000818:Animals; D001682:Biological Availability; D001724:Birth Weight / Q000187:drug effects; D000431:Ethanol / Q000097:blood; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000473:pathology*; D005313:Fetal Death / Q000473:pathology / Q000517:prevention & control*; D005317:Fetal Growth Retardation / Q000473:pathology / Q000517:prevention & control*; D005978:Glutathione / Q000378:metabolism; D008098:Litter Size / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy
D009842:Oligopeptides; C410622:activity-dependent neurotrophic factor; D000431:Ethanol; D005978:Glutathione; C425904:davunetide