Novel peptides prevent alcohol-induced spatial learning deficits and proinflammatory cytokine release in a mouse model of fetal alcohol syndrome.
OBJECTIVE
Previously, the novel peptides NAPVSIPQ and SALLRSIPA were shown to prevent alcohol-induced fetal death and growth abnormalities in a mouse model of fetal alcohol syndrome. This study evaluated whether these peptides could prevent long-term alcohol-induced learning abnormalities. In addition, because specific cytokines are known to effect long-term potentiation, a model of learning at the molecular level, we studied the effect of these novel peptides on tumor necrosis factor-alpha, interleukin-6, and interferon-gamma levels.


METHODS
We used a well-characterized mouse model of fetal alcohol syndrome. Pregnant mice were injected on day 8 with alcohol (0.03 mL/kg) or placebo. Pretreatment with NAPVSIPQ+SALLRSIPA (20 mug) or placebo was given 30 minutes before alcohol. Embryos were removed after 6 hours, at which time cytokine, tumor necrosis factor-alpha, interleukin-6, and interferon-gamma levels were measured with enzyme-linked immunoassays. To test spatial learning, adult offspring from litters that were treated with alcohol, control, NAPVSIPQ+SALLRSIPA then alcohol, or NAPVSIPQ+SALLRSIPA alone were evaluated for latency to find a hidden platform in the Morris water maze.


RESULTS
Alcohol treatment increased tumor necrosis factor-alpha levels versus control levels (50.0 +/- 3.5 pg/mL vs 32.7 +/- 2.4 pg/mL; P < .001). NAPVSIPQ+SALLRSIPA pretreatment prevented this increase (39.9 9 +/- 2.8 pg/mL; P </= .01), with levels similar to control (P=.1). Similarly, alcohol increased interleukin-6 levels versus control levels (22.6 +/- 1.4 pg/mL vs 17.3 +/- 0.6 pg/mL; P < .001), and NAPVSIPQ+SALLRSIPA prevented this increase (19.1 +/- 1.0 pg/mL; P </= .02), with levels similar to control levels (P=.2). Interferon-gamma levels were not different among the 3 groups (alcohol, 14.6 +/- 4.9 pg/mL; control, 17.9 +/- 6.6 pg/mL; alcohol+NAPVSIPQ+SALLRSIPA, 13.6 +/- 4.9 pg/mL; P=.2). In the Morris water maze, alcohol-treated groups did not learn over the 7-day trial compared with the control group (P=.001). Groups that were pretreated with NAPVSIPQ+SALLRSIPA then alcohol learned significantly, which was similar to the control group. Groups that were treated with only NAPVSIPQ+SALLRSIPA learned significantly earlier, with the shortest latency once learning commenced.


CONCLUSIONS
The peptides, NAPVSIPQ+SALLRSIPA, prevented the alcohol-induced spatial learning deficits and attenuated alcohol-induced proinflammatory cytokine increase in a model of fetal alcohol syndrome. This study demonstrates the peptides' significant in vivo efficacy with long-lasting effects obtained after prenatal administration.
Vink
Joy
J
Unit on Perinatal and Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. jyv5y@virginia.edu
Auth
Jonathan
J
Abebe
Daniel T
DT
Brenneman
Douglas E
DE
Spong
Catherine Y
CY
D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D007371:Interferon-gamma / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D007858:Learning / Q000187:drug effects*; D007859:Learning Disabilities / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D009479:Neuropeptides; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; C410622:activity-dependent neurotrophic factor; D000431:Ethanol; D007371:Interferon-gamma; C425904:davunetide