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Behav Brain Res ; 278: 210-20, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25300468


Autism is a neurodevelopmental disorder with multiple genetic and environmental risk factors. Choline is a fundamental nutrient for brain development and high choline intake during prenatal and/or early postnatal periods is neuroprotective. We examined the effects of perinatal choline supplementation on social behavior, anxiety, and repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse model of autism. The BTBR or the more "sociable" C57BL/6J (B6) strain females were fed a control or choline-supplemented diet from mating, throughout pregnancy and lactation. After weaning to a control diet, all offspring were evaluated at one or two ages [postnatal days 33-36 and 89-91] using open field (OF), elevated plus maze (EPM), marble burying (MB), and three-chamber social interaction tests. As expected, control-diet BTBR mice displayed higher OF locomotor activity, impaired social preference, and increased digging behavior during the MB test compared to control-diet B6 mice. Choline supplementation significantly decreased digging behavior, elevated the percentage of open arm entries and time spent in open arms in the EPM by BTBR mice, but had no effect on locomotion. Choline supplementation did not alter social interaction in B6 mice but remarkably improved impairments in social interaction in BTBR mice at both ages, indicating that the benefits of supplementation persist long after dietary choline returns to control levels. In conclusion, our results suggest that high choline intake during early development can prevent or dramatically reduce deficits in social behavior and anxiety in an autistic mouse model, revealing a novel strategy for the treatment/prevention of autism spectrum disorders.

Transtorno Autístico/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Colina/farmacologia , Nootrópicos/farmacologia , Animais , Ansiedade/tratamento farmacológico , Transtorno Autístico/psicologia , Colina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Nootrópicos/administração & dosagem , Gravidez , Comportamento Social , Fatores de Tempo , Resultado do Tratamento
PLoS One ; 9(4): e94287, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24732467


The development of an effective therapy for Alzheimer's disease (AD) is a major challenge to biomedical sciences. Because much of early AD pathophysiology includes hippocampal abnormalities, a viable treatment strategy might be to use trophic factors that support hippocampal integrity and function. IGF2 is an attractive candidate as it acts in the hippocampus to enhance memory consolidation, stimulate adult neurogenesis and upregulate cholinergic marker expression and acetylcholine (ACh) release. We performed a seven-day intracerebroventricular infusion of IGF2 in transgenic APPswe.PS1dE9 AD model mice that express green fluorescent protein in cholinergic neurons (APP.PS1/CHGFP) and in wild type WT/CHGFP littermates at 6 months of age representing early AD-like disease. IGF2 reduced the number of hippocampal Aß40- and Aß42-positive amyloid plaques in APP.PS1/CHGFP mice. Moreover, IGF2 increased hippocampal protein levels of the ACh-synthesizing enzyme, choline acetyltransferase in both WT/CHGFP and APP.PS1/CHGFP mice. The latter effect was likely mediated by increased protein expression of the cholinergic differentiating factor, BMP9, observed in IGF2-treated mice as compared to controls. IGF2 also increased the protein levels of hippocampal NGF, BDNF, NT3 and IGF1 and of doublecortin, a marker of neurogenesis. These data show that IGF2 administration is effective in reversing and preventing several pathophysiologic processes associated with AD and suggest that IGF2 may constitute a therapeutic target for AD.

Doença de Alzheimer/metabolismo , Amiloidose/patologia , Neurônios Colinérgicos/metabolismo , Fator 2 de Diferenciação de Crescimento/metabolismo , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptores de Ativinas Tipo I/metabolismo , Receptores de Activinas Tipo II , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/complicações , Amiloidose/fisiopatologia , Animais , Biomarcadores/metabolismo , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Hipocampo/enzimologia , Hipocampo/patologia , Humanos , Fator de Crescimento Insulin-Like II/administração & dosagem , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese , Neuropeptídeos/metabolismo , Placa Amiloide/complicações , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia