An Open-Label Pilot Study of a Formulation Containing the Anti-Inflammatory Flavonoid Luteolin and Its Effects on Behavior in Children With Autism Spectrum Disorders

Taliou, Anilia; Ζιντζαράς, Ηλίας; Lykouras, Lefteris; Francis, Kostantinos

doi:10.1016/j.clinthera.2013.04.006

Cited by 187 publications

(132 citation statements)

References 43 publications

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“…In vivo, luteolin reversed autism-like behavior in the maternal immune activation mouse model (50,90,91). Moreover, two pilot, open-label, clinical studies using a luteolin-containing dietary formulation reported significant improvement in attention and sociability in children with ASD (51,52). Methoxyluteolin is a more potent inhibitor than luteolin or rapamycin (92) and other mTOR inhibitors (93), indicating that it could be developed into an effective treatment for ASD.…”

Section: Discussionmentioning

confidence: 99%

“…Luteolin also reverses autism-like behavior in mice (50). Two clinical studies further reported that a luteolincontaining dietary formulation significantly improved attention and sociability in children with ASD (51,52). Its structural analog methoxyluteolin (3′,4′,5,7-tetramethoxyflavone) is a more potent mast cell inhibitor (53) and is more metabolically stable (54); hence, it is more likely to reach therapeutic levels in the brain.…”

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confidence: 99%

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

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

104

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We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1β and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1–1 μM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Patel

Tsilioni

Leeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

104

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“…A recent clinical trial reported statistically significant benefits of a luteolin-containing dietary supplement in children with autism (Taliou et al, 2013), many of whom have "allergic-like" symptoms (Theoharides, 2013b), which implicates MC activation (Theoharides et al, 2012b). In fact, flavonoids have recently been discussed as a possible treatment of central nervous system disorders (Jager and Saaby, 2011; Grosso et al, 2013).…”

Section: Treatmentmentioning

confidence: 99%

Fibromyalgia Syndrome in Need of Effective Treatments

Theoharides

Tsilioni

Arbetman

et al. 2015

J Pharmacol Exp Ther

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Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain, affecting primarily women. It is clinically characterized by chronic, nonarticular pain and a heightened response to pressure along with sleep disturbances, fatigue, bowel and bladder abnormalities, and cognitive dysfunction. The diagnostic criteria have changed repeatedly, and there is neither a definitive pathogenesis nor reliable diagnostic or prognostic biomarkers. Clinical and laboratory studies have provided evidence of altered central pain pathways. Recent evidence suggests the involvement of neuroinflammation with stress peptides triggering the release of neurosenzitizing mediators. The management of FMS requires a multidimensional approach including patient education, behavioral therapy, exercise, and pain management. Here we review recent data on the pathogenesis and propose new directions for research and treatment.

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“…Endocrine disruptors, including Bisphenol A and polychlorinated biphenyls , but also dietary phytoestrogens are known to affect neurodevelopment in rodents [163,165] Luteolin and quercetin have been reported to reduce autism symptoms in a small clinical trial [166].…”

Section: Persistent Organic Pollutants (Pop) and Polycyclic Aromatic mentioning

confidence: 99%

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

Carter

Blizard

2016

Neurochemistry International

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An Open-Label Pilot Study of a Formulation Containing the Anti-Inflammatory Flavonoid Luteolin and Its Effects on Behavior in Children With Autism Spectrum Disorders

Cited by 187 publications

References 43 publications

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

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

Fibromyalgia Syndrome in Need of Effective Treatments

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

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