davunetide and Learning-Disabilities

To evaluate whether peptides given to adult mice with Down syndrome prevent learning deficits, and to delineate the mechanisms behind the protective effect.. Ts65Dn mice were treated for 9 days with peptides D-NAPVSIPQ (NAP)+D-SALLRSIPA (SAL) or placebo, and wild-type animals were treated with placebo. Beginning on treatment day 4, the mice were tested for learning using the Morris watermaze. Probe tests for long-term memory were performed on treatment day 9 and 10 days after treatment stopped. Open-field testing was performed before and after the treatment. Calibrator-normalized relative real-time polymerase chain reaction (PCR) with glyceraldehyde-3-phosphate dehydrogenase (GAPD) standardization was performed on the whole brain and hippocampus for activity-dependent neuroprotective protein, vasoactive intestinal peptide (VIP), glial fibrillary acidic protein (GFAP), NR2B, NR2A, and γ-aminobutyric acid type A (GABAA)-α5. Statistics included analysis of variance and the Fisher protected least significant difference, with P<.05 significant.. The Ts65Dn plus placebo animals did not learn over the 5-day period compared with the controls (P<.001). The Ts65Dn +(D-NAP+D-SAL) learned significantly better than the Ts65Dn plus placebo (P<.05), and they retained learning similar to controls on treatment day 9, but not after 10 days of no treatment. Treatment with D-NAP+D-SAL prevented the Ts65Dn hyperactivity. Adult administration of D-NAP+D-SAL prevented changes in activity-dependent neuroprotective protein, intestinal peptide, and NR2B with levels similar to controls (all P<.05).. Adult treatment with D-NAP+D-SAL prevented learning deficit in Ts65Dn, a model of Down syndrome. Possible mechanisms of action include reversal of vasoactive intestinal peptide and activity-dependent neuroprotective protein dysregulation, as well as increasing expression of NR2B, thus facilitating learning.

Topics: Animals; Disease Models, Animal; Down Syndrome; Female; Glial Fibrillary Acidic Protein; Homeodomain Proteins; Learning Disabilities; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Oligopeptides; Peptide Fragments; Vasoactive Intestinal Peptide

To evaluate whether treatment with neuroprotective peptides to young adult mice prenatally exposed to alcohol reverses alcohol-induced learning deficits in a mouse model of fetal alcohol syndrome, whether the mechanism involves the N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid type A (GABAA) receptors, and whether it is related to glial cells.. C57Bl6/J mice were treated with alcohol (0.03 ml/g) or placebo on gestational day 8. On day 40, male mice exposed to alcohol in utero were treated daily for 10 days with D-NAPVSIPQ and D-SALLRSIPA (n=20) or placebo (n=13); and control offspring were treated with placebo (n=46), with the treatment blinded. Learning evaluation began after 3 days using the Morris watermaze and the T-maze. The hippocampus, cortex, and cerebellum were isolated. Expression of NR2A, NR2B, GABAAbeta3, GABAAalpha5, vasoactive intestinal peptide (VIP), activity-dependent neuroprotective protein, and glial fibrillary acidic protein was measured using calibrator-normalized relative real-time polymerase chain reaction. Statistical analysis included analysis of variance and Fisher's protected least significant difference.. Treatment with D-NAPVSIPQ and D-SALLRSIPA reversed the alcohol-induced learning deficit in both learning tests as well as the NR2A and NR2B down-regulation in the hippocampus and the up-regulation of NR2A in the cortex and NR2B in the cortex and cerebellum (all P<.05). No significant differences were found in GABAA expression. Moreover, the peptides changed activity-dependent neuroprotective protein expression in the cortex (P=.016) but not the down-regulation of VIP (P=.883), probably because the peptides are downstream from VIP.. Alcohol-induced learning deficit was reversed and expression of NR2A and NR2B was restored in the hippocampus and cortex of young adult mice treated with D-NAPVSIPQ and D-SALLRSIPA. Given the role of NMDA receptors in learning, this may explain in part the mechanism of prevention of alcohol-induced learning deficits by D-NAPVSIPQ and D-SALLRSIPA.

Topics: Animals; Cerebellum; Cerebral Cortex; Female; Fetal Alcohol Spectrum Disorders; Glial Fibrillary Acidic Protein; Hippocampus; Learning Disabilities; Male; Maze Learning; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuroprotective Agents; Oligopeptides; Peptide Fragments; Pregnancy; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Vasoactive Intestinal Peptide

Prenatal alcohol exposure affects 1 in 100 births in the United States and results in craniofacial dysmorphologic condition and learning disabilities. In a model for fetal alcohol syndrome, neuroprotective peptides prevented fetal death and learning deficits. The gamma-aminobutyric acid A (GABA) receptor subunit GABAbeta3 plays a critical role for nervous system and palate development. Our objective was to determine whether the neuropeptides prevented alcohol-induced damage through GABAbeta3.. With a model for fetal alcohol syndrome, timed pregnant C57B16/J mice were treated on gestational day 8 with alcohol (25% alcohol) or control (saline solution) or alcohol plus peptides NAPVSIPQ + SALLRSIPA (NAP + SAL; 20 microg). Embryos were harvested at 6 and 24 hours and 10 days after treatment. Adult males were tested for learning on the Morris water maze, and their brains were dissected. With samples from at least 3 litters per time point, calibrator-normalized relative real-time polymerase chain reaction was performed for GABAbeta3 with glyceraldehyde-3-phosphate dehydrogenase standardization. Statistical analysis included analysis of variance and Fisher protected least significant difference.. Twenty-four hours and 10 days after treatment, alcohol decreased GABAbeta3 in the embryos (P < or = .01); this decrease was prevented by the peptides (P = .01). GABAbeta3 was higher in alcohol treated adult brains respect to the controls (P = .002); this rise was not prevented by the peptides.. Treatment with the neuropeptides NAPVSIPQ and SALLRSIPA prevented the alcohol-induced decline in GABAbeta3 expression 10 days after alcohol exposure. Because palate formation continues through E18, NAPVSIPQ and SALLRSIPA may be beneficial for the prevention of cleft lip and palate.

Topics: Animals; Cleft Lip; Cleft Palate; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Learning Disabilities; Mice; Mice, Inbred C57BL; Oligopeptides; Pregnancy; Receptors, GABA-A

Vasoactive intestinal peptide (VIP)-related peptides prevented the learning deficit in the offspring in a model for fetal alcohol syndrome. We evaluated whether the mechanism of the peptide protection included NR2B, NR2A, and GABAAalpha5.. Timed, pregnant C57BL6/J mice were injected on gestational day 8 with alcohol (0.03 mL/kg), placebo, or alcohol plus peptides. Embryos were harvested after 6 hours, 24 hours, and on gestational day 18. Some of the litters were allowed to deliver, and the adult brains harvested after the offspring were tested for learning. Calibrator-normalized relative real-time polymerase chain reaction (PCR) was performed using primers for NR2B, NR2A, and GABAAalpha5 with GAPDH standardization. Statistic: analysis of variance (ANOVA) and Fisher PLSD, P < .05 was considered significant.. In the embryo, the peptides prevented NR2B rise (P < .001) at 6 hours, NR2B down-regulation (P = .002), and GABAAalpha5 decrease (P < .01) on gestational day 18. In the adult, the peptides prevented NR2B down-regulation (P = .01) and NR2A up-regulation (P < .001).. VIP-related peptides prevented alcohol-induced changes in NR2B, NR2A, and GABAAalpha5. This may explain, at least in part, the peptides' prevention of alcohol-induced learning deficits.

Topics: Animals; Female; Fetal Alcohol Spectrum Disorders; Learning Disabilities; Mice; Mice, Inbred C57BL; Oligopeptides; Pregnancy; Protein Subunits; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate

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.. 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.. 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

Topics: Animals; Disease Models, Animal; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Interferon-gamma; Interleukin-6; Learning; Learning Disabilities; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuropeptides; Oligopeptides; Pregnancy; Tumor Necrosis Factor-alpha

The prophylactic neuroprotective effects of NAP, a femtomolar-acting neuroprotective peptide were tested in a mouse model of head trauma. NAP was injected for the first 3 weeks of life and head injury was initiated at 4 months. After trauma, mice were tested for their performance by evaluating damaged motor ability, balance and alertness. Comparison of the performance 1 h and 1 week after injury indicated that NAP treatment resulted in faster and enhanced recovery. In a 5-day Morris water maze test with mice suffering moderate to severe injuries, only the NAP-treated group learned to find the hidden platform in the maze. Furthermore, NAP treatment resulted in decreased mRNA expression of the inflammation marker, Mac-1. Thus, a potentially new prophylactic treatment against neurodegeneration is suggested.

Topics: Aging; Animals; Animals, Newborn; Craniocerebral Trauma; Injections, Subcutaneous; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Oligopeptides; Recovery of Function; Trauma Severity Indices; Wounds, Nonpenetrating