Peptide-mediated protection from ethanol-induced neural tube defects.
Ethanol inhibition of L1-mediated cell adhesion may contribute to the spectrum of neurological, behavioral and morphological abnormalities associated with prenatal ethanol exposure. We showed previously that the neuroprotective peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL) antagonize ethanol inhibition of L1 adhesion and prevent ethanol-induced growth retardation in mouse whole embryo culture. Here we ask whether NAP and SAL also prevent ethanol-induced major malformations of the nervous system. Gestational day 8.0 (3-5 somites) C57BL/6J mouse embryos were grown for 6 h in control medium, 100 mM ethanol and 10(-10) M peptides and then maintained for an additional 20 h in control medium. At the end of the culture period, only embryos having 18-19 somite pairs were examined and compared for the degree of neural tube closure. Ethanol exposure resulted in neural tube defects (NTDs) consistent with total dysraphia and anencephaly. Co-incubation with ethanol and L-NAP (all L-amino acids), D-NAP (all D-amino acids) or SAL significantly increased the percentage of embryos that had begun to close their neural folds at the level of the forebrain/midbrain junction or that had progressed beyond this stage of closure. P7A-NAP (NAPVSIAQ), which lacks neuroprotective activity, but retains activity as an antagonist of ethanol inhibition of L1 adhesion, was effective in preventing ethanol-induced NTDs. In contrast, I6A-NAP (NAPVSAPQ), which shows reduced efficacy as an ethanol antagonist but retains its neuroprotective efficacy, did not significantly diminish the induction of NTDs by ethanol. These findings demonstrate the ability of NAP and SAL to prevent ethanol-induced NTDs and support the hypothesis that ethanol teratogenesis is caused in part by ethanol inhibition of L1-mediated cell adhesion.
Chen
Shao-Yu
SY
Bowles Center for Alcohol Studies and Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599-7178, USA. syc@med.unc.edu
Charness
Michael E
ME
Wilkemeyer
Michael F
MF
Sulik
Kathleen K
KK
D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D046149:Embryo Culture Techniques; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D039842:Neural Cell Adhesion Molecule L1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009436:Neural Tube Defects / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011247:Pregnancy
D039842:Neural Cell Adhesion Molecule L1; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010455:Peptides; C502410:seryl-alanyl-leucy-leucyl-arginyl-seryl-isoleucyl-prolyl-alanine; D000431:Ethanol; C425904:davunetide