Prevention of Developmental Delays in a Down Syndrome Mouse Model

Abstract

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.

Reversal of Alcohol-Induced Learning Deficits in the Young Adult in a Model of Fetal Alcohol Syndrome

“…12 In a mouse model for Down syndrome, prenatal treatment with NAPV-SIPQ and SALLRSIPA reversed developmental deficits in newborn pups. 26 In normal animals, NAPV-SIPQ and SALLRSIPA have been shown to enhance learning. 27 However, despite the well-documented neurotrophic and neuroprotective actions of NAPV-SIPQ and SALLRSIPA in numerous abnormalities, the molecular mechanisms and signaling pathways that mediate these effects are not well understood, and recent studies of hippocampal cultures found that activity-dependent neurotrophic factor alters glutamate release and NMDA receptors.…”

Is it possible to improve neurodevelopmental abnormalities in Down syndrome?

“…Consistent with this effect, prenatal treatment (i.p. injections to Ts65Dn pregnant females in the period E8-E12) with NAP (20 µ g) plus SAL (20 µ g) prevents the delay of neurodevelopmental milestones in trisomic offspring (Toso et al, 2008 ). While treatment does not prevent VIP up-regulation, it appears to improve the reduced levels of ADNP.…”

Structure of three Humanin peptides with different activities upon interaction with liposome

“…These peptides were derived by fusing two other neuroprotective peptides, NAP (NAPVSIPQ) and activity-dependent neuroprotective factor-9 (ADNF9, SALLRSIPA). ADNF9 and NAP protect neurons from a variety of neurotoxic insults by unknown mechanisms [35][36][37][38]. Thus, these fusion peptides were prepared to examine their in vitro and in vivo activities.…”