Resveratrol regulates Thoc5 to improve maternal immune activation-induced autism-like behaviors in adult mouse offspring.

Maternal infection during pregnancy is an important cause of autism spectrum disorder (ASD) in offspring, and inflammatory infiltration caused by maternal immune activation (MIA) can cause neurodevelopmental disorders in the fetus. Medicine food homologous (MFH) refers to a traditional Chinese medicine (TCM) concept, which effectively combines food functions and medicinal effects. However, no previous study has screened, predicted, and validated the potential targets of MFH herbs for treating ASD. Therefore, in this study, we used comprehensive bioinformatics methods to screen and analyze MFH herbs and drug targets on a large scale, and identified resveratrol and Thoc5 as the best small molecular ingredient and drug target, respectively, for the treatment of MIA-induced ASD. Additionally, the results of in vitro experiments revealed that resveratrol increased the expression of Thoc5 and effectively inhibited lipopolysaccharide-induced inflammatory factor production by BV2 cells. Moreover, in vivo, resveratrol increased the expression of Thoc5 and effectively inhibited placental and fetal brain inflammation in MIA pregnancy mice, and improved ASD-like behaviors in offspring.

Physical health of autistic girls and women: a scoping review.

BACKGROUND: There is a growing recognition of sex and gender influences in autism. Increasingly, studies include comparisons between sexes or genders, but few have focused on clarifying the characteristics of autistic girls'/women's physical health. METHODS: A scoping review was conducted to determine what is currently known about the physical health of autistic girls/women. We screened 1112 unique articles, with 40 studies meeting the inclusion criteria. We used a convergent iterative process to synthesize this content into broad thematic areas. RESULTS: Autistic girls/women experience more overall physical health challenges compared to non-autistic girls/women and to autistic boys/men. Emerging evidence suggests increased prevalence of epilepsy in autistic girls/women compared to non-autistic girls/women and to autistic boys/men. The literature also suggests increased endocrine and reproductive health conditions in autistic girls/women compared to non-autistic girls/women. Findings regarding gastrointestinal, metabolic, nutritional, and immune-related conditions are preliminary and inconsistent. LIMITATIONS: The literature has substantial heterogeneity in how physical health conditions were assessed and reported. Further, our explicit focus on physical health may have constrained the ability to examine interactions between mental and physical health. The widely differing research aims and methodologies make it difficult to reach definitive conclusions. Nevertheless, in keeping with the goals of a scoping review, we were able to identify key themes to guide future research. CONCLUSIONS: The emerging literature suggests that autistic girls/women have heightened rates of physical health challenges compared to non-autistic girls/women and to autistic boys/men. Clinicians should seek to provide holistic care that includes a focus on physical health and develop a women's health lens when providing clinical care to autistic girls/women.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway.

Autism is characterized by social deficits, communication abnormalities, and repetitive behaviors. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infections by gram-negative bacteria, induces autistic-like behaviors. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected pioglitazone to block or ease the impairments induced by LPS because although this drug was designed as an anti-diabetic drug (it has an insulin effect), it also exerts anti-inflammatory effects. Juvenile offspring were treated daily with pioglitazone, and the main behaviors related to autism, namely, socialization (play behavior) and communication (50-kHz ultrasonic vocalizations), were studied. Biomarkers linked to autism and/or pioglitazone were also studied to attempt to understand the mechanisms involved, namely, IL-6, TNF-alpha, MCP-1, insulin, and leptin. Prenatal LPS exposure induced social deficits and communicational abnormalities in juvenile rat offspring as well as elevated plasma IL-6 levels. Daily postnatal pioglitazone treatment blocked the impairments found in terms of the time spent on social interaction, the number of vocalizations (i.e., autistic-like behaviors) and the elevated plasma IL-6 levels. Thus, pioglitazone appears to be a relevant candidate for the treatment of autism. The present findings may contribute to a better understanding and treatment of autism and associated diseases.

Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features.

The present study was undertaken to elucidate the effect of alpha-linolenic acid (ALA, 18:3, ω-3) and gamma-linolenic acid (GLA, 18:3, ω-6) on experimental autism features induced by early prenatal exposure to valproic acid (VPA) in albino wistar pups. The pups were scrutinized on the accounts of behavioral, biochemical, and inflammatory markers, and the results suggested that the GLA can impart significant protection in comparison to ALA against VPA-induced autism features. When scrutinized histopathologically, the cerebellum of the GLA-treated animals was evident for more marked protection toward neuronal degeneration and neuronal loss in comparison to ALA. Concomitant administration of ALA and GLA with VPA demonstrated a marked cutdown in the Pgp 9.5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect.

Prevention of behavioral deficits in rats exposed to folate receptor antibodies: implication in autism.

Folate receptor alpha (FRα) autoantibodies have been associated with fetal abnormalities and cerebral folate deficiency-related developmental disorders. Over 70% of the children with autism spectrum disorders (ASD) are positive for these autoantibodies and high-dose folinic acid is beneficial in treating these children. Here we show that antibodies (Abs) to the rat FRα administered during gestation produce communication, learning and cognitive deficits in a rat model that can be prevented by folinic acid and dexamethasone. FRα Ab can trigger inflammation as well as block folate transport to the fetus and to the developing brain to produce the functional deficits. In humans, exposure to FRα autoantibodies during fetal development and infancy could contribute to brain dysfunction such as that seen in ASD and other developmental disorders. Identifying women positive for the autoantibody and treating them with high-dose folinic acid along with other interventions to lower the autoantibody titer are effective strategies that may be considered to reduce the risk of having a child with developmental deficits.

A cleanroom sleeping environment's impact on markers of oxidative stress, immune dysregulation, and behavior in children with autism spectrum disorders.

BACKGROUND: An emerging paradigm suggests children with autism display a unique pattern of environmental, genetic, and epigenetic triggers that make them susceptible to developing dysfunctional heavy metal and chemical detoxification systems. These abnormalities could be caused by alterations in the methylation, sulfation, and metalloprotein pathways. This study sought to evaluate the physiological and behavioral effects of children with autism sleeping in an International Organization for Standardization Class 5 cleanroom. METHODS: Ten children with autism, ages 3-12, slept in a cleanroom for two weeks to evaluate changes in toxin levels, oxidative stress, immune dysregulation, and behavior. Before and after the children slept in the cleanroom, samples of blood and hair and rating scale scores were obtained to assess these changes. RESULTS: Five children significantly lowered their concentration of oxidized glutathione, a biomarker of oxidative stress. The younger cohort, age 5 and under, showed significantly greater mean decreases in two markers of immune dysregulation, CD3% and CD4%, than the older cohort. Changes in serum magnesium, influencing neuronal regulation, correlated negatively while changes in serum iron, affecting oxygenation of tissues, correlated positively with age. Changes in serum benzene and PCB 28 concentrations showed significant negative correlations with age. The younger children demonstrated significant improvements on behavioral rating scales compared to the older children. In a younger pair of identical twins, one twin showed significantly greater improvements in 4 out of 5 markers of oxidative stress, which corresponded with better overall behavioral rating scale scores than the other twin. CONCLUSIONS: Younger children who slept in the cleanroom altered elemental levels, decreased immune dysregulation, and improved behavioral rating scales, suggesting that their detoxification metabolism was briefly enhanced. The older children displayed a worsening in behavioral rating scale performance, which may have been caused by the mobilization of toxins from their tissues. The interpretation of this exploratory study is limited by lack of a control group and small sample size. The changes in physiology and behavior noted suggest that performance of larger, prospective controlled studies of exposure to nighttime or 24 hour cleanroom conditions for longer time periods may be useful for understanding detoxification in children with autism. TRIAL REGISTRATION: Clinical Trial Registration Number NCT02195401 (Obtained July 18, 2014).

The interaction between maternal immune activation and alpha 7 nicotinic acetylcholine receptor in regulating behaviors in the offspring.

Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) associated with schizophrenia in clinical studies and rodent models. This study investigates the role of α7nAChR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. We provided choline, a selective α7nAChR agonist among its several developmental roles, in the diet of C57BL/6N wild-type dams throughout the gestation and lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal-placental-fetal axis at mid-gestation were investigated. We found that choline supplementation prevented several MIA-induced behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine interleukin-6 (Il6) and Chrna7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of Il6 in Chrna7 mutant mice. We found that the basal level of Il6 was higher in Chrna7 mutant fetal brain, which suggests that α7nAChR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in Chrna7(+/-) offspring. The Chrna7(+/-) offspring were more vulnerable to MIA, with increased behavioral abnormalities. Our study shows that α7nAChR modulates inflammatory response affecting the fetal brain and demonstrates its effects on offspring behavior development after MIA.

A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder.

Autism, an incurable neurodevelopmental brain disorder, is a complex psychopathology in which the affected individual cannot effectively self-regulate their sensory inputs toward coherent and focused motor outputs. There have been many hypotheses as to the etiology of autism - genetics, neurotransmitter imbalances, early childhood immunizations, xenobiotic and teratogenic agents, and maternal infection; the disorder can perhaps be studied best under the field of "Psychoneuroimmunology", which analyzes systemic and psychopathologies from an integrated approach through the combined effects of the nervous, immune, and endocrine systems. Using principles of psychoneuroimmunology along with previously established but yet un-linked scientific principles and observations, this paper proposes a neuroimmune-based mechanistic hypothesis for the etiology of autism that connects elevated levels of maternal pro-inflammatory cytokines to autistic symptoms in her offspring through a logical sequence of events. While both researchers and clinicians often note correlations between pro-inflammatory cytokine levels and autistic symptoms in affected individuals, no specific mechanism has been documented that logically and directly connects the two. I propose that pro-inflammatory cytokines arising from maternal inflammation, infection, and, possibly, autoimmunity, pass through the placenta; enter the fetal circulation; cross the fetal blood-brain barrier (BBB); and cause aberrant neuronal growth and plasticity within the fetal brain via a "cytokine-storm". Microglia and astrocyte stimulation lead to a positive-feedback loop that also facilitates the development of a chronic inflammatory environment within the fetus, pre-disposing it to lifelong comorbid psychiatric and systemic pathologies. Such a mechanism could account for many of the observed symptoms and behaviors of autistic individuals such as hyper-sensitivity to environmental stimuli, object fixation, echolalia, repetitive physical behaviors, chronic enterocolitis, autoimmune disease, and, at the extreme, savantism. The thiazolidinedione pioglitazone (and possibly rosiglitazone), a non-steroidal anti-inflammatory drug (NSAID), which is commonly used to lower blood glucose levels and associated inflammatory markers in patients with diabetes, and histamine receptor blockers, as well as monitoring and limiting sucrose-containing foods, might prove to be effective preventative therapies for the development of autism in the fetus for pregnant women displaying either a cytokine-induced depression or other elevated systemic inflammatory state conditions.

The review of most frequently occurring medical disorders related to aetiology of autism and the methods of treatment.

The medical understanding of autism has changed since it was first defined by Kanner. Nowadays medicine identifies many medical abnormalities and diseases, which may underline or aggravate the cognitive aspect, behavioural issues and general health in autists. This includes chronic inflammation of gastrointestinal tract, dysbiosis, maldigestion, malabsorption, malnutrition, food intolerance, allergies, chronic viral, fungal and bacterial infections, impaired kidney function, impaired detoxification of endo- and exotoxins, disorders of metal ion transportation. Treatment of the above mentioned conditions combined with improving detoxification mechanisms, followed by a special diet and individually customized supplementation of nutritional deficiencies may lead to the improvement of the functioning of these patients, changing their level of functioning and self-dependence. The aim of this paper is to present medical problems of children with autism which may be identified and treated by general practitioners as a review of current medical papers related to Autism Spectrum Disorder, in the context of author's professional experience, based on the medical cases from author's practice.

Food allergy and autism spectrum disorders: is there a link?

Gastrointestinal (GI) symptoms are common comorbidities in children with autism spectrum disorders (ASDs). Parents often attribute these GI symptoms to food allergy (FA), although an evaluation for IgE-mediated FA is often unrevealing. Our previous studies indicated a high prevalence of non-IgE-mediated FA in young children with ASDs. Therefore, non-IgE-mediated FA may account for some but not all GI symptoms observed in children with ASDs. This raises the question of what treatment measures are applicable to ASD children with GI symptoms. A wide variety of dietary supplements and dietary intervention measures for ASD children have been promoted by medical professionals practicing complementary and alternative medicine despite the lack of rigorous scientific validation in most instances. This review summarizes possible (or proposed) etiologies of GI symptoms in ASD children and discusses risks and possible benefits of intervention measures promoted by complementary and alternative practitioners, with emphasis on FA.

The history of vaccinations in the light of the autism epidemic.

Autism has been characterized as a behavioral disorder since it was first described by Leo Kanner in 1943. The number of autistic children has increased over the last decade. The incidence of autism was 1 in 10000 before the 1970s and has steadily increased to 1 in 150 in 2008 with a male:female predominance of 4:1. The cause of this epidemic has remained unknown, but several hypotheses have been studied. Many of these suggest an environmental trigger, such as the ethyl mercury contained in the preservative thimerosal, which has been used in vaccines since 1931. Other possible triggers associated with vaccinations are chemical toxins and live viruses. James has published studies suggesting a genetic predisposition in the families of autistic children, exposing them to a deficiency in glutathione and an inability to detoxify heavy metals. Vargas has shown autism to encompass ongoing inflammation in the brains of autistic children. The Hannah Poling vaccine decision was a landmark case. Poling's family was awarded funds for ongoing medical care of an autistic child who was found to have mitochondrial dysfunction exacerbated by vaccines that left her with autistic behavior and seizures. Several studies have emerged supporting the fact that a significant number of autistic children do have mitochondrial dysfunction. The impact that the Poling case will have on the ability of parents of autistic children to gain access to funds to enable them to properly care for their children remains to be seen.

A possible central mechanism in autism spectrum disorders, part 1.

The autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders that have been increasing in incidence since the 1980s. Despite a considerable amount of data being collected from cases, a central mechanism has not been offered. A careful review of ASD cases discloses a number of events that adhere to an immunoexcitotoxic mechanism. This mechanism explains the link between excessive vaccination, use of aluminum and ethylmercury as vaccine adjuvants, food allergies, gut dysbiosis, and abnormal formation of the developing brain. It has now been shown that chronic microglial activation is present in autistic brains from age 5 years to age 44 years. A considerable amount of evidence, both experimental and clinical, indicates that repeated microglial activation can initiate priming of the microglia and that subsequent stimulation can produce an exaggerated microglial response that can be prolonged. It is also known that one phenotypic form of microglia activation can result in an outpouring of neurotoxic levels of the excitotoxins, glutamate and quinolinic acid. Studies have shown that careful control of brain glutamate levels is essential to brain pathway development and that excesses can result in arrest of neural migration, as well as dendritic and synaptic loss. It has also been shown that certain cytokines, such as TNF-alpha, can, via its receptor, interact with glutamate receptors to enhance the neurotoxic reaction. To describe this interaction I have coined the term immunoexcitotoxicity, which is described in this article.

Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice.

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.

Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits.

Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

Immunity, neuroglia and neuroinflammation in autism.

Autism is a complex neurodevelopmental disorder of early onset that is highly variable in its clinical presentation. Although the causes of autism in most patients remain unknown, several lines of research support the view that both genetic and environmental factors influence the development of abnormal cortical circuitry that underlies autistic cognitive processes and behaviors. The role of the immune system in the development of autism is controversial. Several studies showing peripheral immune abnormalities support immune hypotheses, however until recently there have been no immune findings in the CNS. We recently demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism, findings that support the view that neuroimmune abnormalities occur in the brain of autistic patients and may contribute to the diversity of the autistic phenotypes. The role of neuroglial activation and neuroinflammation are still uncertain but could be critical in maintaining, if not also in initiating, some of the CNS abnormalities present in autism. A better understanding of the role of neuroinflammation in the pathogenesis of autism may have important clinical and therapeutic implications.

Autism and the immune system.

As our knowledge of the interactions of the immune, nervous and endocrine systems progresses, complex links with the origin and course of psychopathology in childhood are revealed. In this article the neuroimmunological literature on autism is reviewed. Relevant aspects of immune functioning and the neuroendocrine-immune network are described. We present the immunological findings in autistic patients within two related conceptual frameworks: a viral and an autoimmune hypothesis. Interpretation of data is hampered by conceptual and methodological differences between studies. Both the clinical significance of the immune changes and the causal connection between immune changes and psychopathological phenomena in autism remain to be elucidated. Recommendations for further research are given.