[Show abstract][Hide abstract] ABSTRACT: Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Autism spectrum disorders (ASD) are characterized by social and learning disabilities that affect as many as 1/80 children in the USA. There is still no definitive pathogenesis or reliable biomarkers for ASD, thus significantly curtailing the development of effective therapies. Many children with ASD regress at about age 3 years, often after a specific event such as reaction to vaccination, infection, stress or trauma implying some epigenetic triggers, and may constitute a distinct phenotype. ASD children respond disproportionally to stress and are also affected by food and skin allergies. Corticotropin-releasing hormone (CRH) is secreted under stress and together with neurotensin (NT) stimulates mast cells and microglia resulting in focal brain inflammation and neurotoxicity. NT is significantly increased in serum of ASD children along with mitochondrial DNA. NT stimulates mast cell secretion of mitochondrial DNA that is misconstrued as an innate pathogen triggering an auto-inflammatory response. Lack of the mammalian target of rapamycin (mTOR), which is inhibited by the phosphatase and tensin homolog (PTEN), has been linked to gene mutations associated with higher risk of ASD. CRH, NT and environmental triggers could hyperstimulate the already activated mTOR leading to higher risk for ASD, as well as stimulate mast cell and microglia activation and proliferation. The natural flavonoid luteolin inhibits mTOR, mast cells and microglia and could have a significant benefit in ASD.
Journal of Neuroinflammation 04/2013; 10(1):46. DOI:10.1186/1742-2094-10-46 · 5.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by difficulties in communication and by repetitive and stereotypic behaviors, as well as by social impairment, attention, cognitive, and learning defects. ASDs present in early childhood and their prevalence has increased significantly to 1/150 children. Despite a number of theories, the actual reasons for this increase are still not clear. There is no reliable screening test, and no definite pathogenesis or curative therapy. Consequently, there is a major gap hampering development of effective treatments.
To review recent publications on ASDs pathogenesis and treatment with emphasis on neuroimmune processes and new therapeutic approaches.
Mostly original papers (450) on epidemiology, possible pathogenesis or treatment of ASDs in Medline from 1990 to May 2009 were reviewed. All authors contributed to this review.
Increased oxidative stress and immune dysregulation are present in ASDs. Mast-cell activation may contribute to gut-blood-brain barrier disruption and brain inflammation. No effective treatments have emerged. Well-designed clinical trials with nonpsychotropic drugs were few and ASD characteristics varied considerably, making conclusions difficult. Psychotropic drugs are often used for stereotypic and aggressive behaviors. Unique combinations with antioxidant and anti-inflammatory flavonoids hold promise. New potential translational research areas and possible treatments are suggested.
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