Focal brain inflammation and autism

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.

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

“…Immune dysfunction (18,(20)(21)(22) and inflammation of the brain (23)(24)(25) are now invoked in the pathogenesis of ASD. However, the stimuli that promote these inflammatory processes in the brain are presently unknown.…”

Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

“…In addition to multiple sclerosis, neuroinflammation plays a role in the etiology and/or progression also of other CNS diseases. These include Parkinson's disease (Koutsilieri et al 2013), Alzheimer's disease (Fuster-Matanzo et al 2013), bipolar disorder (Stertz et al 2013), and autism (Theoharides et al 2013). In neurodegenerative diseases, one of the mechanisms of progression and damage to healthy neurons in the vicinity of lesions is overactive microglia.…”

Role of Microglia in Autism: Recent Advances

“…Mast cells are capable of migrating across the blood-brain barrier in situations where the barrier is compromised as a result of CNS pathology [61]. The high incidence of autism patients suffering from food or skin allergies [62] suggests the possibility that such mast cell-microglia interactions may contribute to the pathophysiology of neurodevelopmental disorders.…”