RESUMO
OBJECTIVES: Autism spectrum disorder (ASD) is characterized by impairments in social interaction and communication, and by restricted repetitive behaviors and interests. Its etiology is still unknown, but different environmental factors during pregnancy, such as exposure to valproic acid (VPA), are associated with high incidence of ASD in children. In this context, prenatal exposure to VPA in rodents has been used as a reliable model of ASD. Ketogenic diet (KD) is an alternative therapeutic option for refractory epilepsy; however, the effects of this approach in ASD-like behavior need to be evaluated. We conducted a behavioral assessment of the effects of KD in the VPA model of autism. METHODS: Pregnant animals received a single-intraperitoneal injection of 600 mg/kg VPA, and their offspring were separated into four groups: (1) control group with standard diet (C-SD), (2) control group with ketogenic diet (C-KD), (3) VPA group with standard diet (VPA-SD), and (4) VPA group with ketogenic diet (VPA-KD). RESULTS: When compared with the control group, VPA animals presented increased social impairment, repetitive behavior and higher nociceptive threshold. Interestingly, the VPA group fed with KD presented improvements in social behavior. These mice displayed higher scores in sociability index and social novelty index when compared with the SD-fed VPA mice. DISCUSSION: VPA mice chronically exposed to a KD presented behavioral improvements; however, the mechanism by which KD improves ASD-like features needs to be further investigated. In conclusion, the present study reinforces the potential use of KD as a treatment for the core deficits of ASD.
Assuntos
Transtorno do Espectro Autista/prevenção & controle , Dieta Cetogênica , Modelos Animais de Doenças , Animais , Anticonvulsivantes/toxicidade , Ansiedade/etiologia , Ansiedade/prevenção & controle , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Asseio Animal/efeitos dos fármacos , Masculino , Camundongos , Limiar da Dor/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos , Ácido Valproico/toxicidadeRESUMO
Autism spectrum disorders (ASD) consist in a range of neurodevelopmental conditions that share common features with autism, such as impairments in communication and social interaction, repetitive behaviors, stereotypies, and a limited repertoire of interests and activities. Some studies have reported that folic acid supplementation could be associated with a higher incidence of autism, and therefore, we aimed to conduct a systematic review of studies involving relationships between this molecule and ASD. The MEDLINE database was searched for studies written in English which evaluated the relationship between autism and folate. The initial search yielded 60 potentially relevant articles, of which 11 met the inclusion criteria. The agreement between reviewers was κ = 0.808. The articles included in the present study addressed topics related to the prescription of vitamins, the association between folic acid intake/supplementation during pregnancy and the incidence of autism, food intake, and/or nutrient supplementation in children/adolescents with autism, the evaluation of serum nutrient levels, and nutritional interventions targeting ASD. Regarding our main issue, namely the effect of folic acid supplementation, especially in pregnancy, the few and contradictory studies present inconsistent conclusions. Epidemiological associations are not reproduced in most of the other types of studies. Although some studies have reported lower folate levels in patients with ASD, the effects of folate-enhancing interventions on the clinical symptoms have yet to be confirmed.
Assuntos
Transtorno do Espectro Autista/etiologia , Suplementos Nutricionais/efeitos adversos , Medicina Baseada em Evidências , Desenvolvimento Fetal , Ácido Fólico/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Adolescente , Fenômenos Fisiológicos da Nutrição do Adolescente , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/prevenção & controle , Criança , Fenômenos Fisiológicos da Nutrição Infantil , Dieta/efeitos adversos , Feminino , Ácido Fólico/sangue , Ácido Fólico/uso terapêutico , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/dietoterapia , Deficiência de Ácido Fólico/fisiopatologia , Deficiência de Ácido Fólico/prevenção & controle , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/etiologia , Hiper-Homocisteinemia/fisiopatologia , Hiper-Homocisteinemia/prevenção & controle , Incidência , Masculino , Gravidez , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
Rostral fluid displacement has been proposed as a pathophysiologic mechanism of both central and obstructive sleep apnea. Aquaporins are membrane proteins that regulate water transport across the cell membrane and are involved in brain edema formation and resolution. The present study investigated the effect of intermittent hypoxia (IH), a model of sleep apnea, on brain aquaporins. Mice were exposed to intermittent hypoxia to a nadir of 7% oxygen fraction. Brain water content, Aquaporin-1 and Aquaporin-3 were measured in the cerebellum and hippocampus. Hematoxylin-eosin and immunohistochemistry stainings were performed to evaluate cell damage. Compared to the sham group, the hypoxia group presented higher brain water content, lower levels of Aquaporin-1 and similar levels of Aquaporin-3. Immunoreactivity to GFAP and S100B was stronger in the hypoxia group in areas of extensive gliosis, compatible with cytotoxic edema. These findings, although preliminary, indicate an effect of IH on aquaporins levels. Further investigation about the relevance of these data on the pathophysiology of OSA is warranted.
Assuntos
Aquaporinas/metabolismo , Encéfalo/metabolismo , Síndromes da Apneia do Sono/patologia , Animais , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Hipóxia/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Tamanho do Órgão , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/metabolismo , Síndromes da Apneia do Sono/etiologia , Estatísticas não Paramétricas , Água/metabolismoRESUMO
Sleep apnea is a breathing disorder that results from momentary and cyclic collapse of the upper airway, leading to intermittent hypoxia (IH). IH can lead to the formation of free radicals that increase oxidative stress, and this mechanism may explain the association between central sleep apnea and nonalcoholic steatohepatitis. We assessed the level of inflammation in the lung and liver tissue from animals subjected to intermittent hypoxia and simulated sleep apnea. A total of 12 C57BL/6 mice were divided into two groups and then exposed to IH (n = 6) or a simulated IH (SIH) (n = 6) for 35 days. We observed an increase in oxidative damage and other changes to endogenous antioxidant enzymes in mice exposed to IH. Specifically, the expression of multiple transcription factors, including hypoxia inducible factor (HIF-1α), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF-α), inducible NO synthase (iNOS), vascular endothelial growth factor (VEGF), and cleaved caspase 3 were shown to be increased in the IH group. Overall, we found that exposure to intermittent hypoxia for 35 days by simulating sleep apnea leads to oxidative stress, inflammation, and increased activity of caspase 3 in the liver and lung.
Assuntos
Hepatite/etiologia , Hipóxia/complicações , Pneumonia/etiologia , Apneia Obstrutiva do Sono/complicações , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/análise , Estresse Oxidativo , Apneia Obstrutiva do Sono/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
BACKGROUND: Intermittent hypoxia (IH), a model of sleep apnea, produces weight loss in animals. We hypothesized that changes in brown adipose tissue (BAT) function are involved in such phenomenon. We investigated the effect of IH, during 35 days, on body weight, brown adipose tissue wet weight (BATww) and total protein concentration (TPC) of BAT. METHODS: We exposed Balb/c mice to 35 days of IH (n = 12) or sham intermittent hypoxia (SIH; n = 12), alternating 30 seconds of progressive hypoxia to a nadir of 6%, followed by 30 seconds of normoxia. During 8 hours, the rodents underwent a total of 480 cycles of hypoxia/reoxygenation, equivalent to an apnea index of 60/hour. BAT was dissected and weighed while wet. Protein was measured using the Lowry protein assay. RESULTS: Body weight was significantly reduced in animals exposed to IH, at day 35, from 24.4 ± 3.3 to 20.2 ± 2.2 g (p = 0.0004), while in the SIH group it increased from 23.3 ± 3.81 to 24.1 ± 2.96 g (p = 0.23). BATww was also lower in IH than in SIH group (p = 0.00003). TPC of BAT, however, was similar in IH (204.4 ± 44.3 µg/100 µL) and SIH groups (213.2 ± 78.7 µg/100 µL; p = 0.74) and correlated neither with body weight nor with BATww. TPC appeared to be unaffected by exposure to IH also in multivariate analysis, adjusting for body weight and BATww. The correlation between body weight and BATww is significant (rho= 0.63) for the whole sample. When IH and SIH groups are tested separately, the correlations are no longer significant (rho = 0.48 and 0.05, respectively). CONCLUSION: IH during 35 days in a mice model of sleep apnea causes weight loss, BATww reduction, and no change in TPC of BATww. The mechanisms of weight loss under IH demands further investigation.