title: Neuroprotective peptides influence cytokine and chemokine alterations in a model of fetal alcohol syndrome.
abstract: OBJECTIVE
  Fetal alcohol syndrome (FAS) is associated with intellectual disability and neurodevelopmental abnormalities. Neuroprotective peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL) can prevent some of the alcohol-induced teratogenesis including fetal death, growth abnormalities, and learning impairment in part by preventing alcohol-induced alterations in N-methyl-D-aspartate receptor gene expression in a mouse model for FAS. We evaluated a panel of cytokines and chemokines to determine whether NAP plus SAL work through a cytokine/chemokine-mediated pathway in preventing these alterations.
  
  
  METHODS
  Using a well-characterized FAS model, timed, pregnant C57BL6/J mice were treated on gestational day (E) 8 with alcohol (0.03 mL/g), placebo, or alcohol plus peptides. Embryos were evaluated at 2 time points: after 6 hours and 10 days later at E18. A panel of cytokines/chemokines was measured using a microsphere-based multiplex immunoassay (Luminex xMAP; Millipore, Billerica, MA). Statistical analysis included Kruskal-Wallis, with P < .05 considered significant.
  
  
  RESULTS
  Six hours after treatment, interleukin (IL)-6 and keratinocyte chemoattractant cytokine (KC) were not detectable in the control embryos. Alcohol treatment resulted in detectable levels and significant increases in IL-6 (median, 15.7; range, 10.1-45.9 pg/mL) and KC (median, 45.9; range, 32.5-99.1 pg/mL). Embryos exposed to alcohol plus NAP plus SAL had undetectable IL-6 and KC (both P < .003), similar to the controls. Alcohol exposure resulted in a significant increase of granulocyte colony-stimulating factor (G-CSF) (P < .003) as compared with controls, and treatment with NAP plus SAL prevented the alcohol-induced increase. IL-13 and IL-1β were decreased 6 hours after alcohol exposure, and exposure to alcohol plus NAP plus SAL did not completely ameliorate the decrease. At E18, 10 days after exposure, these alterations were no longer present. Several analytes (regulated upon activation, normal T cell expressed, and secreted, tumor necrosis factor-α, interferon-γ, and IL-4) were not detectable at either time point in any of the groups.
  
  
  CONCLUSIONS
  Prenatal alcohol exposure acutely results in a significant elevation of IL-6, G-CSF and the KC, which are known to affect N-methyl-D-aspartate receptors. NAP plus SAL treatment prevented alcohol-induced increases. This provides additional insight into the mechanism of alcohol damage in FAS and NAP plus SAL prevention of neurodevelopmental anomalies.
authors.affiliation: Unit on Perinatal and Developmental Neurobiology, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. robersor@mail.nih.gov
authors.forename: Robin
authors.initials: R
authors.lastname: Roberson
authors.forename: Thea
authors.initials: T
authors.lastname: Kuddo
authors.forename: Ines
authors.initials: I
authors.lastname: Benassou
authors.forename: Daniel
authors.initials: D
authors.lastname: Abebe
authors.forename: Catherine Y
authors.initials: CY
authors.lastname: Spong
mesh_terms: D000818:Animals; D018925:Chemokines / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000188:drug therapy* / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism; D007155:Immunologic Factors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology*; D011247:Pregnancy
chemical_list: D018925:Chemokines; D016207:Cytokines; D007155:Immunologic Factors; D015850:Interleukin-6; D009842:Oligopeptides; C502410:seryl-alanyl-leucy-leucyl-arginyl-seryl-isoleucyl-prolyl-alanine; D016179:Granulocyte Colony-Stimulating Factor; C074302:keratinocyte-derived chemokines; D000431:Ethanol; C425904:davunetide