Peptidergic agonists of activity-dependent neurotrophic factor protect against prenatal alcohol-induced neural tube defects and serotonin neuron loss.
BACKGROUND
Prenatal alcohol exposure via maternal liquid diet consumption by C57BL/6 (B6) mice causes conspicuous midline neural tube deficit (dysraphia) and disruption of genesis and development of serotonin (5-HT) neurons in the raphe nuclei, together with brain growth retardation. The current study tested the hypothesis that concurrent treatment with either an activity-dependent neurotrophic factor (ADNF) agonist peptide [SALLRSIPA, (SAL)] or an activity-dependent neurotrophic protein (ADNP) agonist peptide [NAPVSIPQ, (NAP)] would protect against these alcohol-induced deficits in brain development.


METHODS
Timed-pregnant B6 dams consumed alcohol from embryonic day 7 (E7, before the onset of neurulation) until E15. Fetuses were obtained on E15 and brain sections processed for 5-HT immunocytochemistry, for evaluation of morphologic development of the brainstem raphe and its 5-HT neurons. Additional groups were treated either with SAL or NAP daily from E7 to E15 to assess the potential protective effects of these peptides. Measures of incomplete occlusion of the ventral canal and the frequency and extent of the openings in the rhombencephalon were obtained to assess fetal dysraphia. Counts of 5-HT-immunostained neurons were also obtained in the rostral and caudal raphe.


RESULTS
Prenatal alcohol exposure resulted in abnormal openings along the midline and delayed closure of ventral canal in the brainstem. This dysraphia was associated with reductions in the number of 5-HT neurons both in the rostral raphe nuclei (that gives rise to ascending 5-HT projections) and in the caudal raphe (that gives rise to the descending 5-HT projections). Concurrent treatment of the alcohol-consuming dams with SAL prevented dysraphia and protected against the alcohol-induced reductions in 5-HT neurons in both the rostral and caudal raphe. NAP was less effective in protecting against dysraphia and did not protect against 5-HT loss in the rostral raphe, but did protect against loss in the caudal raphe.


CONCLUSIONS
These findings further support the potential usefulness of these peptides for therapeutic interventions in pregnancies at risk for alcohol-induced developmental deficits. Notably, the ascending 5-HT projections of the rostral raphe have profound effects in regulating forebrain development and function, and the descending 5-HT projections of the caudal raphe are critical for regulating respiration. Protection of the rostral 5-HT-system may help prevent structural and functional deficits linked to abnormal forebrain development, and protection of the caudal systems may also reduce the increased risk for sudden infant death syndrome associated with prenatal alcohol exposure.
Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA. imce100@iupui.edu
Feng C
FC
Zhou
Yuan
Y
Fang
Charles
C
Goodlett
D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D018398:Homeodomain Proteins / Q000819:agonists*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000819:agonists*; D009436:Neural Tube Defects / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides; D009842:Oligopeptides; D010446:Peptide Fragments / Q000627:therapeutic use*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000517:prevention & control; D049188:Prenatal Injuries / Q000139:chemically induced / Q000517:prevention & control; D012119:Respiration / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D016135:Spinal Dysraphism / Q000139:chemically induced / Q000517:prevention & control
C117632:Adnp protein, mouse; D002492:Central Nervous System Depressants; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009842:Oligopeptides; D010446:Peptide Fragments; C410622:activity-dependent neurotrophic factor; D012701:Serotonin; D000431:Ethanol