In conclusion, in uncomplicated pregnancies at 40.0 to 41.6 weeks, oligohydramnios is independently associated with a higher risk of low birth weight centile.
Objective
To estimate whether prenatal treatment with neuroprotective peptides prevent 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 (P) 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 (Ts) mice achieved milestones with a significant delay in 4 of 5 motor and sensory milestones. Ts mice that were prenatally exposed to NAPVSIPQ+SALLRSIPA achieved developmental milestones at the same time as the controls in 3 of 4 motor and 1 of 4 sensory milestones (p<0.01). 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 versus 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 Ts brains, while 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.
A sonographic diagnosis of oligohydramnios carries an increased risk of adverse perinatal outcome, even in low-risk pregnancies after 40 weeks. The trend in amniotic fluid volume reduction does not seem to have prognostic significance.
Down syndrome is the most common genetic cause of mental retardation. Active fragments of neurotrophic factors release by astrocyte under the stimulation of vasoactive intestinal peptide, NAPVSIPQ (NAP) and SALLRSIPA (SAL) respectively, have shown therapeutic potential for developmental delay and learning deficits. Previous work demonstrated that NAP+SAL prevent developmental delay and glial deficit in Ts65Dn that is a well-characterized mouse model for Down syndrome. The objective of this study is to evaluate if prenatal treatment with these peptides prevents the learning deficit in the Ts65Dn mice. Pregnant Ts65Dn female and control pregnant females were randomly treated (intraperitoneal injection) on pregnancy days 8 through 12 with saline (placebo) or peptides (NAP 20 µg +SAL 20 µg) daily. Learning was assessed in the offspring (8–10 months) using the Morris Watermaze, which measures the latency to find the hidden platform (decrease in latency denotes learning). The investigators were blinded to the prenatal treatment and genotype. Pups were genotyped as trisomic (Down syndrome) or euploid (control) after completion of all tests. Statistical analysis: two-way ANOVA followed by Neuman-Keuls test for multiple comparisons, P<0.05 was used to denote statistical significance. Trisomic mice who prenatally received placebo (Down syndrome -placebo; n = 11) did not demonstrate learning over the five day period. DS mice that were prenatally exposed to peptides (Down syndrome-peptides; n = 10) learned significantly better than Down syndrome -placebo (p<0.01), and similar to control-placebo (n = 33) and control-peptide (n = 30). In conclusion prenatal treatment with the neuroprotective peptides (NAP+SAL) prevented learning deficits in a Down syndrome model. These findings highlight a possibility for the prevention of sequelae in Down syndrome and suggest a potential pregnancy intervention that may improve outcome.
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