RESUMEN
BACKGROUND: Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental condition affecting communication, social interaction, and behavior. Evidence suggests that environmental pollutants are associated with ASD incidence. This review aimed to analyze the effect of environmental pollutants on ASD. METHODS: Systematic review and meta-analysis of cohort studies evaluated the association between exposure to environmental pollutants and ASD. We searched COCHRANE CENTRAL, MEDLINE, CINAHL, LILACS, EMBASE, PsycINFO, Web of Science, SciELO, and gray literature from inception to January 2023. The model used for meta-analysis was inverse variance heterogeneity (IVhet). The effect measures were the beta coefficient (ß) and the relative risk (RR) with their 95% confidence intervals (95% CI). Sensitivity analyses were carried out using an instrument to screen or diagnose autism. RESULTS: A total of 5,780 studies were identified; 27 were included in the systematic review, and 22 were included in the meta-analysis. These studies included 1,289,183 participants and 129 environmental pollutants. Individual meta-analyses found a significant association between nitrogen dioxide RR = 1.20 (95% CI: 1.03 to 1.38; I2: 91%), copper RR = 1.08 (95% CI: 1.03 to 1.13; I2: 0%), mono-3-carboxy propyl phthalate ß = 0.45 (95% CI: 0.20 to 0.70; I2: 0%), monobutyl phthalate ß = 0.43 (95% CI: 0.13 to 0.73; I2: 0%) and polychlorinated biphenyl (PCB) 138 RR = 1.84 (95% CI: 1.14 to 2.96; I2:0%) with ASD. Subgroup meta-analyses found a significant association with carbon monoxide RR = 1.57 (95% CI: 1.25 to 1.97; I2: 0%), nitrogen oxides RR = 1.09 (95% CI: 1.04 to 1.15; I2: 34%) and metals RR = 1.13 (95% CI: 1.01 to 1.27; I2:24%). CONCLUSION: This study found positive associations nitrogen dioxide, copper, mono-3-carboxypropyl phthalate, monobutyl phthalate, and PCB 138, and the development of ASD, likewise, with subgroups of pollutants carbon monoxide, nitrogen oxides, and metals. Therefore, it is important to identify these risk factors in children and adolescents to contribute to ASD and identify prevention strategies effectively.
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Trastorno del Espectro Autista , Contaminantes Ambientales , Humanos , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/inducido químicamente , Contaminantes Ambientales/efectos adversos , Contaminantes Ambientales/toxicidad , Factores de Riesgo , Estudios de Cohortes , Exposición a Riesgos Ambientales/efectos adversos , Niño , FemeninoRESUMEN
Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABAA receptors (α5-GABAARs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2'F-R-CH3 could attenuate these changes. SH-053-2'F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2'F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2'F-R-CH3. Despite sex differences, our findings indicate that α5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.
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Efectos Tardíos de la Exposición Prenatal , Receptores de GABA-A , Conducta Social , Ácido Valproico , Animales , Femenino , Ácido Valproico/farmacología , Ratas , Masculino , Embarazo , Receptores de GABA-A/efectos de los fármacos , Dopamina/metabolismo , Trastorno del Espectro Autista/inducido químicamente , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiopatología , Ratas Sprague-Dawley , Regulación Alostérica/efectos de los fármacos , Modelos Animales de Enfermedad , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/fisiopatologíaRESUMEN
Autism spectrum disorder (ASD) exhibits a gender bias, with boys more frequently affected than girls. Similarly, in mouse models induced by prenatal exposure to valproic acid (VPA), males typically display reduced sociability, while females are less affected. Although both males and females exhibit VPA effects on neuroinflammatory parameters, these effects are sex-specific. Notably, females exposed to VPA show increased microglia and astrocyte density during the juvenile period. We hypothesized that these distinct neuroinflammatory patterns contribute to the resilience of females to VPA. To investigate this hypothesis, we treated juvenile animals with intraperitoneal bacterial lipopolysaccharides (LPS), a treatment known to elicit brain neuroinflammation. We thus evaluated the impact of juvenile LPS-induced inflammation on adult sociability and neuroinflammation in female mice prenatally exposed to VPA. Our results demonstrate that VPA-LPS females exhibit social deficits in adulthood, overriding the resilience observed in VPA-saline littermates. Repetitive behavior and anxiety levels were not affected by either treatment. We also evaluated whether the effect on sociability was accompanied by heightened neuroinflammation in the cerebellum and hippocampus. Surprisingly, we observed reduced astrocyte and microglia density in the cerebellum of VPA-LPS animals. These findings shed light on the complex interactions between prenatal insults, juvenile inflammatory stimuli, and sex-specific vulnerability in ASD-related social deficits, providing insights into potential therapeutic interventions for ASD.
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Trastorno del Espectro Autista , Lipopolisacáridos , Efectos Tardíos de la Exposición Prenatal , Conducta Social , Ácido Valproico , Animales , Femenino , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Embarazo , Ratones , Ácido Valproico/efectos adversos , Masculino , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/etiología , Microglía/efectos de los fármacos , Microglía/metabolismo , Modelos Animales de Enfermedad , Conducta Animal/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones Endogámicos C57BLRESUMEN
Bisphenol F (BPF) and Bisphenol S (BPS) are being widely used by the industry with the claim of "safer substances", even with the scarcity of toxicological studies. Given the etiological gap of autism spectrum disorder (ASD), the environment may be a causal factor, so we investigated whether exposure to BPF and BPS during the developmental period can induce ASD-like modeling in adult flies. Drosophila melanogaster flies were exposed during development (embryonic and larval period) to concentrations of 0.25, 0.5, and 1 mM of BPF and BPS, separately inserted into the food. When they transformed into pupae were transferred to a standard diet, ensuring that the flies (adult stage) did not have contact with bisphenols. Thus, after hatching, consolidated behavioral tests were carried out for studies with ASD-type models in flies. It was observed that 1 mM BPF and BPS caused hyperactivity (evidenced by open-field test, negative geotaxis, increased aggressiveness and reproduction of repetitive behaviors). The flies belonging to the 1 mM groups of BPF and BPS also showed reduced cognitive capacity, elucidated by the learning behavior through aversive stimulus. Within the population dynamics that flies exposed to 1 mM BPF and 0.5 and 1 mM BPS showed a change in social interaction, remaining more distant from each other. Exposure to 1 mM BPF, 0.5 and 1 mM BPS increased brain size and reduced Shank immunoreactivity of adult flies. These findings complement each other and show that exposure to BPF and BPS during the development period can elucidate a model with endophenotypes similar to ASD in adult flies. Furthermore, when analyzing comparatively, BPS demonstrated a greater potential for damage when compared to BPF. Therefore, in general these data sets contradict the idea that these substances can be used freely.
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Compuestos de Bencidrilo , Drosophila melanogaster , Endofenotipos , Fenoles , Sulfonas , Animales , Drosophila melanogaster/efectos de los fármacos , Fenoles/toxicidad , Sulfonas/toxicidad , Compuestos de Bencidrilo/toxicidad , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Larva/efectos de los fármacos , Masculino , Femenino , Trastorno del Espectro Autista/inducido químicamenteRESUMEN
Autism spectrum disorder (ASD) is characterized by repetitive behaviors and deficits in social interaction. Its etiology is not completely clear, but both genetic and environmental factors contribute to and influence its development and course. The increased number of autism cases in recent years has been strongly associated with increased exposure to heavy metals. Mercury (Hg) has gained prominence in the scientific literature as a result of its presence as an urban pollutant and well-described neurotoxicity. This review assessed the relationship between Hg exposure in the pre- and post-natal period and ASD. The systematic review identified observational clinical studies and pre-clinical trials in journals indexed in the PubMed, Embase, ProQuest, and LILACS databases. The aim of this study was to investigate the association between exposure to Hg and ASD and to define the critical period of exposure. A total of 57 articles were selected for this review, with 35 articles (61.40%) identifying a positive association between ASD and Hg, while 22 articles (38.60%) did not find the same outcome. The biological samples most used to analyze Hg body burdens were hair (36.84%) and blood (36.84%). Most case-control studies found an increase in Hg levels in individuals with ASD who were exposed to a polluted environment in the post-natal period. Taken together, the studies suggest that these patients have a deficient detoxification system, and this could worsen the symptoms of the disorder. However, new studies addressing the influence of Hg on the post-natal nervous system and its relationship with ASD should be carried out.
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Trastorno del Espectro Autista , Mercurio , Femenino , Humanos , Embarazo , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/inducido químicamente , Exposición a Riesgos Ambientales/efectos adversos , Mercurio/toxicidadRESUMEN
Aim: To evaluate the effects of whey protein (WP) supplementation (1.24 mg/g, 24 days) in rats with autism spectrum disorder (ASD) induced by valproic acid (400 mg/kg, single dose). Materials & methods: Wistar rats (14 days old) were divided into four groups: control, ASD, ASD plus WP and WP. Results: WP increased bacterial diversity and the number of colonies. Bacteria from the Firmicutes phylum were predominantly found in the supplemented groups (p < 0.05). WP also improved the animals' memory in the Y-maze test and decreased the time that male animals spent in the 'solitary chamber' (p < 0.05). Conclusion: WP supplementation positively influenced gut microbiota, along with memory.
Thousands of bacteria live in the human intestine. These bacteria help with many functions in the body and are so important that they can communicate with the brain. When the types and abundance of these bacteria change, brain activity can also change. This may be the case in some children with autism spectrum disorder (ASD), who may have an increase in harmful types of bacteria and a decrease in beneficial types of bacteria in the gut. Whey protein is a commonly used protein supplement for muscle growth. However, many studies have shown its benefits for gut bacteria. The authors investigated the effects of whey protein in animals with symptoms of ASD and showed that supplementation with whey protein increased the number of beneficial bacteria. In addition, the rats given whey protein had better memory. ASD-induced rats were less sociable, spending more time by themselves. However, male animals treated with whey protein spent less time alone. Supplementation with whey protein was beneficial for gut bacteria and memory in rats.
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Trastorno del Espectro Autista , Trastorno Autístico , Microbioma Gastrointestinal , Masculino , Ratas , Animales , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Proteína de Suero de Leche , Ácido Valproico/farmacología , Ratas Wistar , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/microbiología , Bacterias , Suplementos DietéticosAsunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Complicaciones del Embarazo , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Humanos , Litio/efectos adversos , Litio/análisis , Trastorno Autístico/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Exposición a Riesgos Ambientales/análisis , Trastorno del Espectro Autista/inducido químicamente , Complicaciones del Embarazo/tratamiento farmacológicoRESUMEN
The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.
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Antipsicóticos , Trastorno del Espectro Autista , Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Ratas , Masculino , Animales , Humanos , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Olanzapina/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Ácido Valproico/farmacología , Ácido Valproico/uso terapéutico , Neuronas , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Conducta Animal , Conducta SocialRESUMEN
Paracetamol (PAR) is an over-the-counter analgesic/antipyretic used during pregnancy worldwide. Epidemiological studies have been associating gestational PAR exposure with neurobehavioral alterations in the progeny resembling autism spectrum disorders and attention-deficit hyperactivity disorder symptoms. The endocannabinoid (eCB) dysfunction was previously hypothesized as one of the modes of action by which PAR may harm the developing nervous system. We aimed to evaluate possible effects of gestational exposure to PAR on male and female rat's offspring behavior and if an acute injection of WIN 55,212-2 (WIN, 0.3 mg/kg), a non-specific cannabinoid agonist, prior to behavioral tests, would induce different effects in PAR exposed and non-exposed animals. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. Nest-seeking, open field, apomorphine-induced stereotypy, marble burying and three-chamber tests were conducted in 10-, 24-, 25- or 30-days-old rats, respectively. PAR exposure resulted in increased apomorphine-induced stereotyped behavior and time spent in the central area of the open field in exposed female pups. Additionally, it induced hyperactivity in the open field and increased marble burying behavior in both male and female pups. WIN injection modified the behavioral response only in the nest seeking test, and opposite effects were observed in control and PAR-exposed neonate females. Reported alterations are relevant for the neurodevelopmental disorders that have been associated with maternal PAR exposure and suggest that eCB dysfunction may play a role in the action by which PAR may harm the developing brain.
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Trastorno del Espectro Autista , Efectos Tardíos de la Exposición Prenatal , Humanos , Embarazo , Ratas , Animales , Masculino , Femenino , Agonistas de Receptores de Cannabinoides/efectos adversos , Acetaminofén/toxicidad , Apomorfina , Ratas Wistar , Endocannabinoides , Trastorno del Espectro Autista/inducido químicamente , Carbonato de Calcio/efectos adversos , Efectos Tardíos de la Exposición Prenatal/inducido químicamenteRESUMEN
Aims: Exposure to endocrine-disrupting chemicals (EDCs) during critical neurodevelopmental windows has been associated with the risk of autistic traits. This systematic review of epidemiological studies examined the association between maternal exposure to EDCs during pregnancy and the risk of autism spectrum disorder (ASD) in the offspring. Methods: We searched PubMed, Web of Science, Scopus, and Google Scholar from inception to November 17, 2022, for studies investigating the association between prenatal exposure to EDCs and outcomes related to ASD. Two independent reviewers screened studies for eligibility, extracted data, and assessed the risk of bias. The review was registered in PROSPERO (CRD42023389386). Results: We included 27 observational studies assessing prenatal exposure to phthalates (8 studies), polychlorinated biphenyls (8 studies), organophosphate pesticides (8 studies), phenols (7 studies), perfluoroalkyl substances (6 studies), organochlorine pesticides (5 studies), brominated flame retardants (3 studies), dioxins (1 study), and parabens (1 study). The number of examined children ranged from 77 to 1,556, the age at the assessment of autistic traits ranged from 3 to 14 years, and most studies assessed autistic traits using the Social Responsiveness Scale. All but one study was considered to have a low risk of bias. Overall, there was no association between maternal exposure to specific ECDs during pregnancy and the occurrence of autistic traits in offspring. Conclusions: Findings from the epidemiological studies evaluated here do not support an association between prenatal exposure to ECDs and the likelihood of autistic traits in later in life. These findings should not be interpreted as definitive evidence of the absence of neurodevelopment effects of EDCs affecting ASD risk, given the limitations of current studies such as representative exposure assessment, small sample sizes, inadequacy to assess sexually dimorphic effects, or the effects of EDC mixtures. Future studies should carefully address these limitations.
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Trastorno del Espectro Autista , Trastorno Autístico , Disruptores Endocrinos , Plaguicidas , Efectos Tardíos de la Exposición Prenatal , Niño , Embarazo , Femenino , Humanos , Adolescente , Preescolar , Disruptores Endocrinos/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/epidemiología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/epidemiología , Plaguicidas/efectos adversos , Estudios EpidemiológicosRESUMEN
Intergenerational transmission of the effects of environmental factors on brain function and behavior can occur through epigenetic mechanisms. Valproic acid (VPA) is an anticonvulsant drug that, when administered during pregnancy, causes various birth defects. The mechanisms of action are largely unclear: VPA can reduce neuronal excitability, but it also inhibits the histone deacetylases, affecting gene expression. Here we evaluated whether the effects of valproic acid prenatal exposure on autism spectrum disorder (ASD)-related behavioral phenotypes can be transmitted to the second generation (F2) through the paternal or the maternal lineage. Indeed, we found that F2 males of the VPA pedigree show reduced sociability, which can be rescued by exposing the animals to social enrichment. Moreover, as is the case for F1 males, F2 VPA males show increased c-Fos expression in the piriform cortex. However, F3 males show normal sociability, indicating that VPA's effects on this behavior are not transgenerationally inherited. Female behavior is not affected by VPA exposure, and we found no evidence of maternal transmission of the consequences of this pharmacological treatment. Finally, all animals exposed to VPA and their descendants show reduced body weight, highlighting an intriguing effect of this compound on metabolism. We propose the VPA model of ASD as a valuable mouse model to study the role of epigenetic inheritance and its underlying mechanisms affecting behavior and neuronal function.
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Trastorno del Espectro Autista , Efectos Tardíos de la Exposición Prenatal , Embarazo , Humanos , Masculino , Ratones , Femenino , Animales , Ácido Valproico , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/genética , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Anticonvulsivantes/toxicidad , Conducta Social , Conducta Animal , Modelos Animales de EnfermedadRESUMEN
Abstract Background: Conventional dental care is often impossible in patients with Autism Spectrum Disorder (ASD). Non-collaborative behaviors, sometimes associated with aggressiveness, are usual justifications for premedication in this population. Thereby, this research focuses on the effects of oral midazolam versus oral ketamine plus midazolam as preanesthetic medication in ASD. Methods: The sample included 64 persons with ASD, aged 2-59 years, scheduled for dental care under general anesthesia. The primary objective of this study was to compare degrees of sedation between two parallel, double-blinded, equally proportional groups randomized to receive oral midazolam (0.5 mg.kg−1, maximum 15 mg) or oral midazolam (0.5 mg.kg−1) associated with oral S(+)-ketamine (3 mg.kg−1, maximum 300 mg). The secondary outcomes were the need of physical stabilization to obtain intravenous line, awakening time, and occurrence of adverse events. Results: According to the dichotomous analysis of sedation level (Ramsay score 1 and 2 versus Ramsay ≥ 3), oral association of S(+)-ketamine and midazolam improved sedation, with increased probability of Ramsay ≥ 3, Relative Risk (RR) = 3.2 (95% Confidence Interval [95% CI] = 1.32 to 7.76) compared to midazolam alone. Combined treatment also made it easier to obtain venous access without physical stabilization, RR = 2.05 (95% CI = 1.14 to 3.68). There were no differences between groups regarding awakening time and the occurrence of adverse events. Conclusion: The association of oral S(+)-ketamine with midazolam provides better preanesthetic sedation rates than midazolam alone and facilitates intravenous line access in patients with autism.
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Humanos , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Ketamina , Medicación Preanestésica , Midazolam , Método Doble Ciego , Sedación Consciente , Hipnóticos y SedantesRESUMEN
OBJECTIVES: To assess the effectiveness and safety of risperidone and aripiprazole in children with autism spectrum disorder (ASD). DESIGN AND SETTING: Overview of systematic reviews (SRs). SEARCH METHODS: In October 2021, we searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycInfo and Epistemonikos placing no restrictions on language or date of publication. PARTICIPANTS: Children aged 12 years or less with ASD. INTERVENTIONS: Risperidone and aripiprazole with no dosage restrictions. DATA COLLECTION AND ANALYSIS: We rated the methodological quality of the included SRs using A Measurement Tool to Assess Systematic Reviews (AMSTAR 2). We reported the Grading of Recommendations, Assessment, Development and Evaluation certainty of the evidence according to the analysis conducted by the authors of the included SRs. MAIN OUTCOMES MEASURED: A multidisciplinary group of experts agreed on analysing nine critical outcomes evolving core and non-core ASD symptoms. PATIENT AND PUBLIC INVOLVEMENT: Organisations of parents of children with ASD were involved during part of the process, participating in external revision of the final version of the report for the Chilean Ministry of Health with no additional comments (ID 757-22-L120 DIPRECE, Ministry of Health, Chile). The organisations involved were: Fundación Unión Autismo y Neurodiversidad, Federación Nacional de Autismo, Vocería Autismo del Sur, and Vocería Autismo del Norte. RESULTS: We identified 22 SRs within the scope of this overview, of which 16 were of critically low confidence according to AMSTAR 2 and were excluded from the analysis. Both aripiprazole and risperidone were effective for reducing autism symptoms severity, repetitive behaviours, inappropriate language, social withdrawal and behavioural problems compared with placebo. The certainty of the evidence for most outcomes was moderate. Risperidone and aripiprazole are associated with metabolic and neurological adverse events. Follow-up was short termed. CONCLUSIONS: We found that aripiprazole and risperidone probably reduce symptom severity at short-term follow-up but may also cause adverse events. High-quality and updated SRs and larger randomised controlled trials with longer term follow-up are needed on this topic. OVERVIEW PROTOCOL: PROSPERO CRD42020206535.
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Trastorno del Espectro Autista , Risperidona , Niño , Humanos , Aripiprazol/uso terapéutico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/inducido químicamente , Risperidona/uso terapéutico , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUND: Conventional dental care is often impossible in patients with Autism Spectrum Disorder (ASD). Non-collaborative behaviors, sometimes associated with aggressiveness, are usual justifications for premedication in this population. Thereby, this research focuses on the effects of oral midazolam versus oral ketamine plus midazolam as preanesthetic medication in ASD. METHODS: The sample included 64 persons with ASD, aged 2-59 years, scheduled for dental care under general anesthesia. The primary objective of this study was to compare degrees of sedation between two parallel, double-blinded, equally proportional groups randomized to receive oral midazolam (0.5 mg.kg-1, maximum 15 mg) or oral midazolam (0.5 mg.kg-1) associated with oral S(+)-ketamine (3 mg.kg-1, maximum 300 mg). The secondary outcomes were the need of physical stabilization to obtain intravenous line, awakening time, and occurrence of adverse events. RESULTS: According to the dichotomous analysis of sedation level (Ramsay score 1 and 2 versus Ramsay ≥ 3), oral association of S(+)-ketamine and midazolam improved sedation, with increased probability of Ramsay ≥ 3, Relative Risk (RR) = 3.2 (95% Confidence Interval [95% CI] = 1.32 to 7.76) compared to midazolam alone. Combined treatment also made it easier to obtain venous access without physical stabilization, RR = 2.05 (95% CI = 1.14 to 3.68). There were no differences between groups regarding awakening time and the occurrence of adverse events. CONCLUSION: The association of oral S(+)-ketamine with midazolam provides better preanesthetic sedation rates than midazolam alone and facilitates intravenous line access in patients with autism.
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Trastorno del Espectro Autista , Ketamina , Humanos , Midazolam , Medicación Preanestésica , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/inducido químicamente , Sedación Consciente , Método Doble Ciego , Hipnóticos y SedantesRESUMEN
Antipsychotics are commonly prescribed to treat several neuropsychiatric disorders, including schizophrenia, mania in bipolar disorder, autism spectrum disorder, delirium, and organic or secondary psychosis, for example, in dementias such as Alzheimer's disease. There is evidence that typical antipsychotics such as haloperidol are more effective in reducing positive symptoms than negative symptoms and/or cognitive deficits. In contrast, atypical antipsychotic agents have gained popularity over typical antipsychotics, due to fewer extrapyramidal side effects and their theoretical efficacy in controlling both positive and negative symptoms. Although these therapies focus on neuron-based therapeutic schemes, glial cells have been recognized as important regulators of the pathophysiology of neuropsychiatric disorders, as well as targets to improve the efficacy of these drugs. Glial cells (astrocytes, oligodendrocytes, and microglia) are critical for the central nervous system in both physiological and pathological conditions. Astrocytes are the most abundant glial cells and play important roles in brain homeostasis, regulating neurotransmitter systems and gliotransmission, since they express a wide variety of functional receptors for different neurotransmitters. In addition, converging lines of evidence indicate that psychiatric disorders are commonly associated with the triad neuroinflammation, oxidative stress, and excitotoxicity, and that glial cells may contribute to the gliotoxicity process. Conversely, glioprotective molecules attenuate glial damage by generating specific responses that can protect glial cells themselves and/or neurons, resulting in improved central nervous system (CNS) functioning. In this regard, resveratrol is well-recognized as a glioprotective molecule, including in clinical studies of schizophrenia and autism. This review will provide a summary of the dual role of antipsychotics on neurochemical parameters associated with glial functions and will highlight the potential activity of glioprotective molecules to improve the action of antipsychotics.
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Antipsicóticos , Trastorno del Espectro Autista , Esquizofrenia , Humanos , Antipsicóticos/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Haloperidol/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/inducido químicamente , NeuroglíaRESUMEN
OBJECTIVE: The aim of this study was to evaluate the influence of early exposure to agricultural pesticides and their relationship with autism spectrum disorder. DATA SOURCE: This systematic review was registered at PROSPERO as CRD42020204842. The subject was systematically analyzed on PubMed, Scopus, and Web of Science databases until April 2021. Only studies with humans with early exposure to agricultural pesticides and diagnosis of autism were included. Exclusion criteria were studies on pesticides for domestic or veterinary use and late exposure. There were no language and time restriction. The quality analysis of the studies used the Newcastle-Ottawa Scale. DATA SYNTHESIS: Six case-control studies were included; three of them measured the route of exposure by maternal biomarkers and the others by the residence address. The studies had scores between moderate and high in the quality assessment tool. It was found high rates of association between early exposure to agricultural pesticides and autism and detection limit above the quantification for a sample of polychlorinated biphenyls, hexachlorobenzene, and dichlorodiphenyldichloroethylene. CONCLUSIONS: There is evidence concerning the exposure to agricultural pesticides in early life and the development of the autism spectrum disorder; however, more studies are required to better understand their possible association.
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Trastorno del Espectro Autista , Trastorno Autístico , Plaguicidas , Bifenilos Policlorados , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/epidemiología , Estudios de Casos y Controles , Humanos , Plaguicidas/toxicidadRESUMEN
Environmental factors acting on young animals affect neurodevelopmental trajectories and impact adult brain function and behavior. Psychiatric disorders may be caused or worsen by environmental factors, but early interventions can improve performance. Understanding the possible mechanisms acting upon the developing brain could help identify etiological factors of psychiatric disorders and enable advancement of effective therapies. Research has focused on the long-lasting effects of environmental factors acting during the perinatal period, therefore little is known about the impact of these factors at later ages when neurodevelopmental pathologies such as autism spectrum disorder (ASD) are usually diagnosed. Here we show that handling mice during the juvenile period can rescue a range of behavioral and cellular effects of prenatal valproic acid (VPA) exposure. VPA-exposed animals show reduced sociability and increased repetitive behaviors, along with other autism-related endophenotypes such as increased immobility in the forced swim test and increased neuronal activity in the piriform cortex (Pir). Our results demonstrate that briefly handling mice every other day between postnatal days 22 and 34 can largely rescue these phenotypes. This effect can also be observed when animals are analyzed across tests using an "autism" factor, which also discriminates between animals with high and low Pir neuron activity. Thus, we identified a juvenile developmental window when environmental factors can determine adult autism-related behavior. In addition, our results have broader implications on behavioral neuroscience, as they highlight the importance of adequate experimental design and control of behavioral experiments involving treating or testing young animals.
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Trastorno del Espectro Autista , Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Animales , Trastorno del Espectro Autista/inducido químicamente , Trastorno Autístico/inducido químicamente , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Embarazo , Ácido Valproico/efectos adversosRESUMEN
METHODS: We searched seven databases and found 13 eligible controlled trials that use omega-3 supplementation in children and adolescents with ASD.Data extraction: We collected details on study design, intervention time, supplement dosage, and the autism assessment scale. Meta-analyses and subgroup analysis were conducted according to the autism symptoms. RESULTS: Omega-3 and omega-6 supplementation improved ASD symptoms according to the Aberrant Behavior Checklist (standard mean difference - SMD = -0.13; CI 95% = -0.34, -0.02). However, using subgroup analysis, we observed no efficacy in terms of improvements in hyperactivity (SMD = -0.03; CI 95%: -0.43, 0.36), irritability (SMD = -0.18; CI 95%: -0.51, 0.15), stereotypy (SMD = -0.03; CI 95%: -0.43, 0.36), inappropriate speech (SMD = -0.68; CI 95%: -1.49, 0.14), lethargy (SMD = -0.22; CI 95%: -0.58, 0.14), and social function (SMD = -0.71; IC 95%: -1.56, 0.14). W-3 and w-6 supplementation also showed no efficacy according to the Social Responsiveness Scale (SMD = 0.08; CI 95%: -0.23, 0.39). The adverse effects were classified as mild and equally distributed between the placebo and intervention groups. CONCLUSIONS: Despite w-3 and w-6 supplementation showing minimal beneficial effects in the treatment of autism, the subgroup analyses indicated that there is a lack of evidence on the beneficial role of w-3 and w-6 in treating ASD.Systematic Review Registration: PROSPERO number CRD42020146116.
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Trastorno del Espectro Autista , Trastorno Autístico , Ácidos Grasos Omega-3 , Trastorno de Movimiento Estereotipado , Adolescente , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Niño , Suplementos Dietéticos , HumanosRESUMEN
Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by movement and social deficits with rapidly increasing incidence worldwide. Propionic acid (PPA) is a histone deacetylase inhibitor that regulates neuronal plasticity in the brain. Evaluation of the behavioral and cellular consequences of PPA exposure during a critical neurodevelopmental window is required. Therefore, in the present study we aimed to evaluate the effects of prenatal PPA exposure on locomotor behavior and astrocyte number, as well as on levels of nitric oxide (NO), synaptophysin (SYP; a marker of synaptic plasticity), and metallothionein 3 (MT-III; a marker of reactive oxygen species and zinc metabolism), in the prefrontal cortex (PFC) of male rats. All parameters were evaluated at three critical ages of development: postnatal days (PD) 21 (weaning age), PD35 (pre-pubertal age) and PD70 (post-pubertal age). Prenatal PPA exposure induced hypolocomotion and decreased rearing events at weaning age. Moreover, astrogliosis in the PFC was observed in PPA-treated rats at pre- and post-pubertal age. SYP levels were dramatically decreased in PPA-treated rats with simultaneous astrogliosis, suggesting reduced synaptic plasticity. MT-III expression was deregulated in PPA-treated rats. Finally, the expression of NO in the PFC remained unaltered in PPA-treated rats. These results mimic behavioral, neuronal and astrocytic characteristics observed in ASD patients.
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Gliosis/inducido químicamente , Gliosis/patología , Locomoción/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Propionatos/toxicidad , Factores de Edad , Animales , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/patología , Femenino , Locomoción/fisiología , Masculino , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Atypical connectivity between brain regions and altered structure of the corpus callosum (CC) in imaging studies supports the long-distance hypoconnectivity hypothesis proposed for autism spectrum disorder (ASD). The aim of this study was to unveil the CC ultrastructural and cellular changes employing the valproic acid (VPA) rat model of ASD. Male Wistar rats were exposed to VPA (450 mg/kg i.p.) or saline (control) during gestation (embryonic day 10.5), and maturation, exploration, and social behavior were subsequently tested. Myelin content, ultrastructure, and oligodendroglial lineage were studied in the CC at post-natal days 15 (infant) and 36 (juvenile). As a functional outcome, brain metabolic activity was determined by positron emission tomography. Concomitantly with behavioral deficits in juvenile VPA rats, the CC showed reduced myelin basic protein, conserved total number of axons, reduced percentage of myelinated axons, and aberrant and less compact arrangements of myelin sheath ultrastructure. Mature oligodendrocytes decreased and oligodendrocyte precursors increased in the absence of astrogliosis or microgliosis. In medial prefrontal and somatosensory cortices of juvenile VPA rats, myelin ultrastructure and oligodendroglial lineage were preserved. VPA animals exhibited global brain hypometabolism and local hypermetabolism in brain regions relevant for ASD. In turn, the CC of infant VPA rats showed reduced myelin content but preserved oligodendroglial lineage. Our findings indicate that CC hypomyelination is established during infancy and prior to oligodendroglial pattern alterations, which suggests that axon-oligodendroglia communication could be compromised in VPA animals. Thus, CC hypomyelination may underlie white matter alterations and contribute to atypical patterns of connectivity and metabolism found in ASD.