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Open Access Highly Accessed Review

Focal brain inflammation and autism

Theoharis C Theoharides1345*, Shahrzad Asadi12 and Arti B Patel16

Author Affiliations

1 Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Suite J304, 136 Harrison Avenue, Boston, MA 02111, USA

2 Department of Pharmacy, Tufts Medical Center, Boston, MA 02111, USA

3 Department of Biochemistry, Tufts University School of Medicine, Boston, MA, USA

4 Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA

5 Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA

6 Graduate Program in Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA

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Journal of Neuroinflammation 2013, 10:46  doi:10.1186/1742-2094-10-46

Published: 9 April 2013

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 (mtDNA). NT stimulates mast cell secretion of mtDNA that is misconstrued as an innate pathogen triggering an auto-inflammatory response. The phosphatase and tensin homolog (PTEN) gene mutation, associated with the higher risk of ASD, which leads to hyper-active mammalian target of rapamycin (mTOR) signalling that is crucial for cellular homeostasis. CRH, NT and environmental triggers could hyperstimulate the already activated mTOR, 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.