Rudimar dos Santos Riesgo

Animal model of autism induced by prenatal exposure to valproate: Behavioral changes and liver parameters

Autism is characterized by behavioral impairments in three main domains: social interaction; language, communication and imaginative play; and range of interests and activities. This syndrome has attracted social attention by its high prevalence. The animal model induced by prenatal exposure to valproic acid (VPA) has been proposed to study autism. Several characteristics of behavioral abnormalities found in the VPA rats, such as repetitive/stereotypic-like activity and deficit in social interaction have been correlated with autism. Features like flexibility to change strategy, social memory and metabolic status of the induced rats have not been examined. Thus, the main aim of this work was to investigate additional behavioral rodent similarities with autism, as well as, liver redox parameters after prenatal exposure to VPA. Young rats from the VPA group presented aberrant approach to a stranger rat, decreased conditioned place preference to conspecifics, normal spatial learning and a lack of flexibility to change their strategy. As adults, they presented inappropriate social approach to a stranger rat, decreased preference for social novelty, apparently normal social recognition and no spatial learning deficits. Examination of the liver from the VPA group presented significantly increased (12%) levels of catalase (CAT) activity, no alteration in superoxide dismutase (SOD) activity and a decrease in the SOD/CAT ratio. TBARS, sulfhydril and carbonyl contents, and serum levels of aminotransferases remained unchanged. In summary, rats prenatally exposed to VPA presented decreased flexibility to change strategy and social impairments similar to the autism symptoms, contributing to the understanding of neurodevelopmental symptoms and oxidative imbalance associated to the autism spectrum disorder.

Effects of relational music therapy on communication of children with autism: a randomized controlled study

The intent of this study (registration ACTRN12608000625370) was to investigate the effects of Relational Music Therapy (RMT) in verbal, nonverbal and social communication of children with autism spectrum disorders (ASDs). A randomized controlled trial (RCT) with 24 boys from the Programme for Invasive Developmental Disorders (Porto Alegre City, Brazil), was designed to compare individuals treated with music therapy (n = 12) and standard treatment (clinical routine activities including medical examinations and consultations, n = 12). The outcomes were assessed by two blind evaluators, before and after interventions, through the verbal, nonverbal and social communication scores of Brazilian version of the Childhood Autism Rating Scale (CARS-BR). The CARS-BR scores in T1 and T2 did not show a statistically significant difference in the three measured outcomes. However, the study found a positive statistically significant difference on subgroup analysis of nonverbal communication among patients with autistic disorder, p = 0.008 and standard mean difference of 2.22 (95% CI 1.90 to 2.53). The results observed in the investigation of the effects of relational music therapy on communication skills of ASD children are inconclusive. The next investigations need more rigorous designs leading to smaller effect size estimates and more accurate tools for the outcome assessment (including some specific instrument of music therapy). These modifications will increase the accuracy to observe the treatment effects in this population.

Childhood autism : translation and validation of the Childhood Autism Rating Scale for use in Brazil

OBJECTIVE To translate the Childhood Autism Rating Scale into Brazilian Portuguese and to determine the initial psychometric properties of the resulting version (CARS-BR). METHODS The methodology used to produce an adequate version included translation, backtranslation and evaluation of semantic equivalence. In order to determine its psychometric properties (internal consistency, validity and reliability), the CARS-BR was administered to 60 consecutive patients with autism, aged between 3 and 17 years and seen at a university hospital. RESULTS Internal consistency was high, with a Cronbachs alpha of 0.82. Convergent validity, in comparison with the Autistic Traits Assessment Scale, exhibited a Pearsons correlation coefficient of r = 0.89. When correlated with the Global Assessment of Functioning Scale in order to evaluate discriminant validity, the CARS-BR exhibited a Pearsons coefficient of r = -0.75. Test-retest reliability exhibited a kappa coefficient of 0.90. CONCLUSION These results suggest that the CARS-BR is a valid and reliable instrument for evaluating autism severity in Brazil.

Animal model of autism induced by prenatal exposure to valproate: Altered glutamate metabolism in the hippocampus

Autism spectrum disorders (ASD) are characterized by deficits in social interaction, language and communication impairments and repetitive and stereotyped behaviors, with involvement of several areas of the central nervous system (CNS), including hippocampus. Although neurons have been the target of most studies reported in the literature, recently, considerable attention has been centered upon the functionality and plasticity of glial cells, particularly astrocytes. These cells participate in normal brain development and also in neuropathological processes. The present work investigated hippocampi from 15 (P15) and 120 (P120) days old male rats prenatally exposed to valproic acid (VPA) as an animal model of autism. Herein, we analyzed astrocytic parameters such as glutamate transporters and glutamate uptake, glutamine synthetase (GS) activity and glutathione (GSH) content. In the VPA group glutamate uptake was unchanged at P15 and increased 160% at P120; the protein expression of GLAST did not change neither in P15 nor in P120, while GLT1 decreased 40% at P15 and increased 92% at P120; GS activity increased 43% at P15 and decreased 28% at P120; GSH content was unaltered at P15 and had a 27% increase at P120. These data highlight that the astrocytic clearance and destination of glutamate in the synaptic cleft might be altered in autism, pointing out important aspects to be considered from both pathophysiologic and pharmacological approaches in ASD.

The Impact of Neuroimmune Alterations in Autism Spectrum Disorder

Autism spectrum disorder (ASD) involves a complex interplay of both genetic and environmental risk factors, with immune alterations and synaptic connection deficiency in early life. In the past decade, studies of ASD have substantially increased, in both humans and animal models. Immunological imbalance (including autoimmunity) has been proposed as a major etiological component in ASD, taking into account increased levels of pro-inflammatory cytokines observed in postmortem brain from patients, as well as autoantibody production. Also, epidemiological studies have established a correlation of ASD with family history of autoimmune diseases; associations with major histocompatibility complex haplotypes and abnormal levels of immunological markers in the blood. Moreover, the use of animal models to study ASD is providing increasing information on the relationship between the immune system and the pathophysiology of ASD. Herein, we will discuss the accumulating literature for ASD, giving special attention to the relevant aspects of factors that may be related to the neuroimmune interface in the development of ASD, including changes in neuroplasticity.

Resveratrol prevents social deficits in animal model of autism induced by valproic acid.

Autism spectrum disorders (ASD) involve a complex interplay of both genetic and environmental risk factors, such as prenatal exposure to valproic acid (VPA). Considering the neuroprotective, antioxidant and anti-inflammatory effects of resveratrol (RSV), we investigated the influence of prenatal RSV treatment on social behaviors of a rodent model of autism induced by prenatal exposure to VPA. In the three-chambered apparatus test, the VPA group showed a reduced place preference conditioned by conspecific and no preference between exploring a wire-cage or a rat enclosed inside a wire cage, revealing sociability impairments. Prenatal administration of RSV prevented the VPA-induced social impairments evaluated in this study. A bioinformatics analysis was used to discard possible molecular interactions between VPA and RSV during administration. The interaction energy between RSV and VPA is weak and highly unstable, suggesting cellular effects instead of a single chemical process. In summary, the present study highlights a promising experimental strategy to evaluate new molecular targets possibly involved in the etiology of autism and developmental alterations implicated in neural and behavioral impairments in ASD.

Effects of an H3R Antagonist on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R) are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX), an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA). Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg) or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data.

Translation and validation of Autism Diagnostic Interview-Revised (ADI-R) for autism diagnosis in Brazil

OBJECTIVE To translate into Brazilian Portuguese the Autism Diagnostic Interview-Revised (ADI-R), an extremely useful diagnostic tool in autism. METHODS A case-control study was done to validate the ADI-R. After being translated, the interview was applied in a sample of 20 patients with autism and 20 patients with intellectual disability without autism, in order to obtain the initial psychometric properties. RESULTS The internal consistency was high, with a of Crombach of 0.967. The validity of criterion had sensitivity and specificity of 100%, having as a gold standard the DSM-IV diagnostic criteria. The interview had high discriminant validity, with higher scores in the group of patients with autism, as well as high interobserver consistency, with median kappa of 0.824. CONCLUSION The final version of ADI-R had satisfactory psychometric characteristics, indicating good preliminary validation properties. The instrument needs to be applied in bigger samples in other areas of the country.

Atypical neuroleptic risperidone modulates glial functions in C6 astroglial cells

Risperidone has demonstrated therapeutic advantages over conventional neuroleptics and offers a valuable emerging option for the treatment of social behavior associated with autistic disorder. Considering the putative involvement of astroglial cells in neuropsychiatric disorders, we investigated the effect of risperidone on parameters of astrocyte activity - glutamate uptake, glutamine synthetase (GS) activity and glutathione (GSH) levels. Risperidone was able to induce a significantly increase on glutamate uptake (32%); GS activity (15%); GSH levels (58%). These findings imply the perspectives for further investigations directed on astrocytes from different brain areas. Our present results suggest that risperidone might exert its neuroprotective effects against brain illness at least partially via modulation of astrocyte functions.

Influence of the 5-HTTLPR polymorphism and environmental risk factors in a Brazilian sample of patients with autism spectrum disorders

The 5-HTTLPR polymorphism of serotonin transporter gene is widely investigated in association studies in autism spectrum disorders (ASD). The results of such studies, however, remain controversial possibly due to the great genetic heterogeneity related to ASD and the lack of evaluation of the triallelic functional structure of 5-HTTLPR. This study tested for association between the 5-HTTLPR and ASD in a Brazilian sample by case-control and family-based association test (FBAT) methods, considering the biallelic and triallelic structures of this polymorphism. In addition, we performed an exploratory analysis of associations between specific clinical outcomes of ASD patients and 5-HTTLPR as well as several prenatal environmental factors. Genotyping was achieved in 151 ASD patients, 179 unrelated controls and 105 complete trios. There was no evidence of association between the 5-HTTLPR with ASD in both case-control and FBAT tests, but the LaLa 5-HTTLPR genotype was associated with mood instability in patients (P=0.006). The prenatal exposure to potential neuroteratogenic drugs was associated with epilepsy (P<0.001). Our findings suggest that the 5-HTTLPR is not associated with ASD in the Brazilian population, even considering the triallelic structure. Additionally, this study suggested a role of the 5-HTTLPR and environmental factors in the clinical expression of ASD.