RESUMO
OBJECTIVE: Previous work has demonstrated that two synthetic peptides can prevent prenatal alcohol-induced damage as assessed by prevention of learning abnormalities in adult offspring as well as improve outcome from traumatic brain damage. The current studies were undertaken to evaluate whether these peptides could enhance performance in a learning and memory paradigm when administered either prenatally or to aged mice. STUDY DESIGN: For prenatal treatment, C57Bl6/J mice were treated on gestational day 8 with 1 oral administration of D-NAP or D-SAL alone or D-NAP+D-SAL or a double dose of D-SAL. Control groups were same-regimen treated with vehicle alone. Learning was assessed in adult male offspring (35-50 days) by using the Morris water maze. To evaluate aged animals, 12-month-old mice were treated with D-NAP and D-SAL or vehicle alone daily and tested on the Morris water maze. RESULTS: Offspring exposed prenatally to D-NAP+D-SAL learned significantly faster than controls, with an earlier onset of learning and an overall decreased latency to find the hidden platform (P < .05). Animals exposed prenatally to either D-NAP or D-SAL alone learned similar to control, with a trend toward faster latencies. Aged animals who received D-NAP+D-SAL learned significantly faster than age-matched controls, with an earlier onset of learning (P < .05). CONCLUSION: Combined D-NAP+D-SAL enhanced learning in healthy young mice and aged mice. These findings suggest potential therapeutic interventions not only during a critical developmental period, but also in aged animals.
Assuntos
Aprendizagem em Labirinto/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/farmacologia , Neuropeptídeos/fisiologia , Oligopeptídeos/fisiologia , GravidezRESUMO
Vasoactive intestinal peptide (VIP) regulates growth in the early post-implantation embryo. Previous work has demonstrated that peptide agonists (SALLRSIPA and NAPVSIPQ) from downstream mediators that are regulated by VIP were able to prevent the alcohol-induced fetal death, growth restriction and microcephaly associated with fetal alcohol syndrome. Here we evaluated the role of VIP in this mouse model of fetal alcohol syndrome, to determine if fetal or maternal levels of VIP are altered. In addition, we evaluated whether peptide treatment would alter the effects of alcohol on VIP levels. Treatment groups included control, alcohol, and alcohol+peptides. VIP levels were measured with enzyme immunoassay [EIA] (Peninsula Laboratories, Belmont, CA). Quantitation of VIP expression was measured with rt-PCR using mimic cDNA primers. Embryo/decidual VIP levels were similar in control and alcohol-treated groups 6 h after treatment. However, in the embryo/deciduas at 12 and 24 h, VIP levels were below the EIA's detection limit in the alcohol-treated groups, and significantly lower than the control or peptide-pretreated groups (p<0.05). Maternal cortex VIP levels were undetectable and significantly lower in the alcohol-treated group than control or peptide+alcohol group at 6 and 12 h (p<0.001). VIP mRNA expression was quantitated in the embryo and deciduas, with a significant decline noted at 6 h to 58% of control levels (p=0.02). Pretreatment with the peptides attenuated the alcohol-induced decrease in VIP mRNA. These studies demonstrate that treatment with alcohol can decrease the expression and immunoreactivity of VIP in both maternal and fetal tissues. This alcohol-induced loss of a recognized regulator of embryonic growth and differentiation may contribute to the sequelae of toxicity observed in fetal alcohol syndrome.
Assuntos
Transtornos do Espectro Alcoólico Fetal/genética , Regulação da Expressão Gênica no Desenvolvimento , Transcrição Gênica , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Morte Fetal , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Idade Gestacional , Troca Materno-Fetal , Camundongos , Gravidez , RNA Mensageiro/genéticaRESUMO
Vasoactive intestinal peptide (VIP) is a regulator of rodent embryogenesis during the period of neural tube closure. VIP enhanced growth in whole cultured mouse embryos; treatment with a VIP antagonist during embryogenesis inhibited growth and development. VIP antagonist treatment during embryogenesis also had permanent effects on adult brain chemistry and impaired social recognition behavior in adult male mice. The neurological deficits of autism appear to be initiated during neural tube closure and social behavior deficits are among the key characteristics of this disorder that is more common in males and is frequently accompanied by mental retardation. The current study examined the blockage of VIP during embryogenesis as a model for the behavioral deficits of autism. Treatment of pregnant mice with a VIP antagonist during embryonic days 8 through 10 had no apparent effect on the general health or sensory or motor capabilities of adult offspring. However, male offspring exhibited reduced sociability in the social approach task and deficits in cognitive function, as assessed through cued and contextual fear conditioning. Female offspring did not show these deficiencies. These results suggest that this paradigm has usefulness as a mouse model for aspects of autism as it selectively impairs male offspring who exhibit the reduced social behavior and cognitive dysfunction seen in autism. Furthermore, the study indicates that the foundations of some aspects of social behavior are laid down early in mouse embryogenesis, are regulated in a sex specific manner and that interference with embryonic regulators such as VIP can have permanent effects on adult social behavior.
Assuntos
Transtorno Autístico/metabolismo , Encéfalo/embriologia , Transtornos Cognitivos/metabolismo , Transtornos Mentais/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Transtorno Autístico/etiologia , Transtorno Autístico/fisiopatologia , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Feminino , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/fisiologia , Masculino , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/fisiopatologia , Camundongos , Peptídeos/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Caracteres Sexuais , Olfato/efeitos dos fármacos , Olfato/fisiologia , Comportamento Social , Peptídeo Intestinal Vasoativo/antagonistas & inibidoresRESUMO
OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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 = .01), with levels similar to control (P=.1). Similarly, alcohol increased interleukin-6 levels versus control levels (22.6 +/- 1.4 pg/mL vs 17.3 +/- 0.6 pg/mL; P < .001), and NAPVSIPQ+SALLRSIPA prevented this increase (19.1 +/- 1.0 pg/mL; P = .02), with levels similar to control levels (P=.2). Interferon-gamma levels were not different among the 3 groups (alcohol, 14.6 +/- 4.9 pg/mL; control, 17.9 +/- 6.6 pg/mL; alcohol+NAPVSIPQ+SALLRSIPA, 13.6 +/- 4.9 pg/mL; P=.2). In the Morris water maze, alcohol-treated groups did not learn over the 7-day trial compared with the control group (P=.001). Groups that were pretreated with NAPVSIPQ+SALLRSIPA then alcohol learned significantly, which was similar to the control group. Groups that were treated with only NAPVSIPQ+SALLRSIPA learned significantly earlier, with the shortest latency once learning commenced. CONCLUSION: The peptides, NAPVSIPQ+SALLRSIPA, prevented the alcohol-induced spatial learning deficits and attenuated alcohol-induced proinflammatory cytokine increase in a model of fetal alcohol syndrome. This study demonstrates the peptides' significant in vivo efficacy with long-lasting effects obtained after prenatal administration.
Assuntos
Etanol/farmacologia , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Aprendizagem/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Oligopeptídeos/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Interferon gama/análise , Interleucina-6/análise , Deficiências da Aprendizagem/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/uso terapêutico , Neuropeptídeos , Oligopeptídeos/uso terapêutico , Gravidez , Fator de Necrose Tumoral alfa/análiseRESUMO
The most common genetic cause of mental retardation is Down syndrome, trisomy of chromosome 21, which is accompanied by small stature, developmental delays, and mental retardation. In the Ts65Dn segmental trisomy mouse model of Down syndrome, the section of mouse chromosome 16 most homologous to human chromosome 21 is trisomic. This model exhibits aspects of Down syndrome including growth restriction, delay in achieving developmental milestones, and cognitive dysfunction. Recent data link vasoactive intestinal peptide malfunction with developmental delays and cognitive deficits. Blockage of vasoactive intestinal peptide during rodent development results in growth and developmental delays, neuronal dystrophy, and, in adults, cognitive dysfunction. Also, vasoactive intestinal peptide is elevated in the blood of newborn children with autism and Down syndrome. In the current experiments, vasoactive intestinal peptide binding sites were significantly increased in several brain areas of the segmental trisomy mouse, including the olfactory bulb, hippocampus, cortex, caudate/putamen, and cerebellum, compared with wild-type littermates. In situ hybridization for VIP mRNA revealed significantly more dense vasoactive intestinal peptide mRNA in the hippocampus, cortex, raphe nuclei, and vestibular nuclei in the segmental trisomy mouse compared with wild-type littermates. In the segmental trisomy mouse cortex and hippocampus, over three times as many vasoactive intestinal peptide-immunopositive cells were visible than in wild-type mouse cortex. These abnormalities in vasoactive intestinal peptide parameters in the segmental trisomy model of Down syndrome suggest that vasoactive intestinal peptide may have a role in the neuropathology of Down-like cognitive dysfunction.