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      Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin

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          Abstract

          Brain “fog” is a constellation of symptoms that include reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory. Brain “fog” characterizes patients with autism spectrum disorders (ASDs), celiac disease, chronic fatigue syndrome, fibromyalgia, mastocytosis, and postural tachycardia syndrome (POTS), as well as “minimal cognitive impairment,” an early clinical presentation of Alzheimer's disease (AD), and other neuropsychiatric disorders. Brain “fog” may be due to inflammatory molecules, including adipocytokines and histamine released from mast cells (MCs) further stimulating microglia activation, and causing focal brain inflammation. Recent reviews have described the potential use of natural flavonoids for the treatment of neuropsychiatric and neurodegenerative diseases. The flavone luteolin has numerous useful actions that include: anti-oxidant, anti-inflammatory, microglia inhibition, neuroprotection, and memory increase. A liposomal luteolin formulation in olive fruit extract improved attention in children with ASDs and brain “fog” in mastocytosis patients. Methylated luteolin analogs with increased activity and better bioavailability could be developed into effective treatments for neuropsychiatric disorders and brain “fog.”

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          Most cited references187

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          The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.

          Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.
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            The development of allergic inflammation.

            Allergic disorders, such as anaphylaxis, hay fever, eczema and asthma, now afflict roughly 25% of people in the developed world. In allergic subjects, persistent or repetitive exposure to allergens, which typically are intrinsically innocuous substances common in the environment, results in chronic allergic inflammation. This in turn produces long-term changes in the structure of the affected organs and substantial abnormalities in their function. It is therefore important to understand the characteristics and consequences of acute and chronic allergic inflammation, and in particular to explore how mast cells can contribute to several features of this maladaptive pattern of immunological reactivity.
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              Elevated immune response in the brain of autistic patients.

              This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD.
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                Author and article information

                Contributors
                URI : http://loop.frontiersin.org/people/23129/overview
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                03 July 2015
                2015
                : 9
                : 225
                Affiliations
                [1] 1Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine Boston, MA, USA
                [2] 2Departments of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center Boston, MA, USA
                [3] 3Psychiatry, Tufts University School of Medicine and Tufts Medical Center Boston, MA, USA
                [4] 4Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine Boston, MA, USA
                [5] 5Second Department of Internal Medicine, Attikon General Hospital, Athens Medical School Athens, Greece
                [6] 6Department of Child Psychiatry, University of Athens Medical School, Aghia Sophia Children's Hospital Athens, Greece
                Author notes

                Edited by: Tommaso Cassano, University of Foggia, Italy; Luca Steardo, Sapienza University of Rome, Italy

                Reviewed by: Masaaki Murakami, Hokkaido University, Japan; Pio Conti, University of Chieti, Italy

                *Correspondence: Theoharis C. Theoharides, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, 136 Harrison Avenue, Suite J304, Boston, MA 02111, USA theoharis.theoharides@ 123456tufts.edu

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2015.00225
                4490655
                26190965
                3ff5c9b7-0f18-4da3-86b5-0c6b5ad9529f
                Copyright © 2015 Theoharides, Stewart, Hatziagelaki and Kolaitis.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 April 2015
                : 10 June 2015
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 222, Pages: 11, Words: 10213
                Funding
                Funded by: US NIH
                Award ID: NS71361
                Funded by: Autism Research Institute
                Funded by: Mastocytosis Society
                Funded by: Johnson Botsford Johnson Fnd
                Funded by: BHARE Fnd
                Funded by: Michael and Katherine Johnson Family Fnd
                Funded by: National Autism Association and Safe Minds
                Categories
                Pharmacology
                Review

                Neurosciences
                brain,cognition,cytokines,fog,histamine,inflammation,luteolin,mast cells
                Neurosciences
                brain, cognition, cytokines, fog, histamine, inflammation, luteolin, mast cells

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