Prevention of developmental delays in a Down syndrome mouse model.
OBJECTIVE
To estimate whether prenatal treatment with neuroprotective peptides prevents the developmental delay and the glial deficit in the Ts65Dn mouse model for Down syndrome and to explore the peptides' effects on achievement of normal development.


METHODS
Pregnant Ts65Dn females were randomly assigned to NAPVSIPQ+SALLRSIPA or control and were treated by investigators blinded to treatment and genotype on gestational days 8-12. Offspring were tested from postnatal day 5 to 21 for motor and sensory milestones with standardized tests by operators blinded to the pup's treatment and genotype. The pup's genotype was determined after completion of all tests. Activity-dependent neurotrophic factor, glial fibrillary acidic protein, and vasoactive intestinal peptide expression were determined using real-time polymerase chain reaction.


RESULTS
Trisomic mice achieved milestones with a significant delay in four of five motor and sensory milestones. Trisomic mice that were prenatally exposed to NAPVSIPQ+SALLRSIPA achieved developmental milestones at the same time as the controls in three of four motor and one of four sensory milestones (P<.01). Euploid pups prenatally treated with NAPVSIPQ+SALLRSIPA achieved developmental milestones significantly earlier than the euploid pups prenatally treated with placebo. Activity-dependent neurotrophic factor expression was significantly downregulated in the Ts65Dn brains compared with the controls, prenatal treatment with NAPVSIPQ+ SALLRSIPA prevented the activity-dependent neurotrophic factor decrease in the Ts65Dn brains, and the expression was not different from the controls. The glial marker glial fibrillary acidic protein demonstrated the known glial deficit in the Ts65Dn mice, and treatment with NAPVSIPQ+ SALLRSIPA prevented its downregulation. Lastly, vasoactive intestinal peptide levels were increased in the trisomic brains, whereas treatment with NAPVSIPQ+SALLRSIPA did not prevent its upregulation.


CONCLUSIONS
Prenatal treatment with NAPVSIPQ and SALLRSIPA prevented developmental delay and the glial deficit in Down syndrome. These findings highlight a possibility for the prevention of developmental sequelae in Down syndrome and suggest a potential intervention during pregnancy that may improve the outcome.
Toso
Laura
L
From the Unit on Perinatal and Developmental Neurobiology, Eunice Kennedy Shriver National Institute of Child and Human Development, National Institutes of Health, Bethesda, Maryland; the Department of Obstetrics and Gynecology, George Washington University, Washington, DC; and the Department of Obstetrics and Gynaecology, University of Milano-Bicocca, Ospedale S. Gerardo, Monza, Italy.
Cameroni
Irene
I
Roberson
Robin
R
Abebe
Daniel
D
Bissell
Stephanie
S
Spong
Catherine Y
CY
D000818:Animals; D000831:Animals, Newborn; D002658:Developmental Disabilities / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007263:Infusions, Parenteral; D051379:Mice; D009419:Nerve Tissue Proteins / Q000008:administration & dosage*; D009457:Neuroglia / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009842:Oligopeptides / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000008:administration & dosage*; D011247:Pregnancy; D011295:Prenatal Care
D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C526732:SALLRSIPA; C425904:davunetide