Abstract
The prevalence of autism spectrum disorder (ASD) continues to increase, but no distinct pathogenesis or effective treatment are known yet. The presence of many comorbidities further complicates matters, making a personalized approach necessary. An increasing number of reports indicate that inflammation of the brain leads to neurodegenerative changes, especially during perinatal life, “short-circuiting the electrical system” in the amygdala that is essential for our ability to feel emotions, but also regulates fear. Inflammation of the brain can result from the stimulation of mast cells—found in all tissues including the brain—by neuropeptides, stress, toxins, and viruses such as SARS-CoV-2, leading to the activation of microglia. These resident brain defenders then release even more inflammatory molecules and stop “pruning” nerve connections, disrupting neuronal connectivity, lowering the fear threshold, and derailing the expression of emotions, as seen in ASD. Many epidemiological studies have reported a strong association between ASD and atopic dermatitis (eczema), asthma, and food allergies/intolerance, all of which involve activated mast cells. Mast cells can be triggered by allergens, neuropeptides, stress, and toxins, leading to disruption of the blood–brain barrier (BBB) and activation of microglia. Moreover, many epidemiological studies have reported a strong association between stress and atopic dermatitis (eczema) during gestation, which involves activated mast cells. Both mast cells and microglia can also be activated by SARS-CoV-2 in affected mothers during pregnancy. We showed increased expression of the proinflammatory cytokine IL-18 and its receptor, but decreased expression of the anti-inflammatory cytokine IL-38 and its receptor IL-36R, only in the amygdala of deceased children with ASD. We further showed that the natural flavonoid luteolin is a potent inhibitor of the activation of both mast cells and microglia, but also blocks SARS-CoV-2 binding to its receptor angiotensin-converting enzyme 2 (ACE2). A treatment approach should be tailored to each individual patient and should address hyperactivity/stress, allergies, or food intolerance, with the introduction of natural molecules or drugs to inhibit mast cells and microglia, such as liposomal luteolin.
Highlights
autism spectrum disorder (ASD) is characterized by difficulties in communication and apparently purposeless repetitive movements [1,2,3,4,5]
With respect to children infected with SARS-CoV-2, even though they have milder pulmonary symptoms than adults [85,86,87,88,89,90,91], a number of papers have reported the presence of Multisystem Inflammatory Syndrome in children (MISC) [92,93,94] and adolescents [95]
We reported that children born to mothers with systemic mastocytosis [63], which is characterized by a greater number of hyperactive mast cells than in the general population [197], had a higher risk of developing ASD [1,2,7,198,199]
Summary
ASD is characterized by difficulties in communication and apparently purposeless repetitive movements [1,2,3,4,5]. Most children with ASD have a number of comorbidities such as hyperactivity, gastrointestinal problems, allergies, and seizures [12,13,14], making the development of effective treatments difficult and prompting the need for a personalized approach [15]. A number of risk factors during gestation [16], especially pre-eclampsia [17,18,19], preterm birth, and low birth weight [20,21,22], as well as atopic conditions, autoimmune diseases, [23,24,25] infection, and psychological stress, have been increasingly associated with higher risk of ASD in the offspring (Table 1) [26,27]. The present manuscript is organized in different parts, stressing certain risk factors such as SARS-CoV2 infection, psychological stress, atopic conditions, and treatment approaches
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