Background: Most neurodegenerative and other brain disorders, especially Myalgic encephalomyelitis/
chronic fatigue syndrome (ME/CFS) and autism spectrum disorder (ASD) continue to elude
objective biomarkers and effective treatments. Increasing evidence indicates that such diseases involve
focal inflammation of the brain.
Objective: To review the role of cytokine-neuropeptide interactions in the pathogenesis of inflammation
of the brain and the beneficial role of natural flavonoids.
Methods: Medline search was conducted (2000-2017) for articles using the terms allergy, amygdala,
atopy, autism, brain, chemokines, cytokines, hypothalamus, immunity, inflammation, mast cells, microglia,
neurotensin, peptides, substance P, and TNF.
Results: Neuropeptides and cytokine stimulation of mast cells and microglia can result in focal inflammation
in the hypothalamus and amygdala, thus explaining most of the symptoms at least in ME/CFS
and ASD. Some of the triggers may be corticotropin-releasing hormone (CRH), neurotensin (NT), and
substance P (SP), which have synergistic action on IL-33. The natural flavonoids luteolin and
tetramethoxyluteolin inhibit these processes and have neuroprotective actions. Tetramethoxyluteolin is
also more metabolically stable and has greater oral absorption.
Conclusion: Inhibition of inflammatory processes unique to the brain with intranasal formulations of
tetramethoxyluteolin could provide new possibilities for the understanding and treatment of neurodegenerative