Theoharis C. Theoharides

Biography

Dr. Theoharides is Professor of Pharmacology, Internal Medicine and Psychiatry, as well as Director of Molecular Immunopharmacology and Drug Discovery at Tufts University School of Medicine, Boston, MA. He was born in Thessaloniki, where he graduated from Anatolia College. He received all his degrees with Honors from Yale University, and was awarded the Dean’s Research Award and the Winternitz Price in Pathology. He trained in internal medicine at New England Medical Center, which awarded him the Oliver Smith Award “recognizing excellence, compassion and service.” He also received a Certificate in Global Leadership from the Tufts Fletcher School of Law and Diplomacy, and a Fellowship at the Harvard Kennedy School of Government. He has been serving as the Clinical Pharmacologist of the Massachusetts Drug Formulary Commission since 1986. In Greece, he has served on the Supreme Advisory Health Councils of the Ministries of Health and of Social Welfare, as well as on the Board of Directors of the Institute of Pharmaceutical Research and Technology. He is a member of 15 academies and scientific societies. He was inducted into the Alpha Omega Alpha National Medical Honor Society and the Rare Diseases Hall of Fame.  He has received the Tufts Alumni Award for Faculty Excellence, the Tufts Distinguished Faculty Recognition Award, Boston Mayor’s Community Award, and the Dr. George Papanicolau Award, as well as Honorary Doctor of Medicine from Athens University and Honorary Doctor of Sciences from Hellenic-American University.  He is “Archon” of the Ecumenical Patriarchate of Constantinople. He first showed that mast cells, known for causing allergic reactions, are critical for inflammation, especially in the brain, and most recently in the pathogenesis of autism. He has published 375 papers (JBC, JACI, JPET, NEJM, Nature, PNAS, Science & Translational Psychiatry) and 3 textbooks with 23,011 citations (h-factor 73) and he is in the top 5% of authors most cited in pharmacological and immunological journals. He has received 37 patents and trademarks, including three covering brain inflammation and autism: US 8,268,365 (09/18/12); US 9,050,275 (06/09/15); US 9,176,146 (11/03/15), and has developed the dietary supplements BrainGain®, NeuroProtek® and NeuroProtek®-Low Phenol.

Neurotensin-Induced Mast Cell and Microglia Stimulation and Brain Inflammation Offers Effective Treatment Target in Autism

Abstract

Autism Spectrum Disorders (ASD) remain without effective treatment due to the lack of distinct pathogenesis and objective biomarkers. In addition to the typical symptoms of ASD, many children have allergic problems, including food intolerance and the risk for developing autism was ten higher in children with mastocytosis than the general population. We first published that most ASD children have high serum levels of two brain peptides secreted under stress, corticotropin-releasing hormone (CRH) and neurotensin (NT), which synergistically trigger mast cells, responsible for allergies.  Stimulated mast cells then release inflammatory molecules (IL-6, IL-17,TNF), found to be high in the brains of children with ASD and trigger microglia to proliferate and release pro-inflammatory molecules. NT also directly stimulates microglia to release IL-1beta and MCP-1, a chemoattractant for mast cells, found to be high in amniotic fluid of children who later developed autism.  Stimulation of both mast cell and microglia is mediated through activation of the mammalian target of rapamycin (mTOR), which is dysregulated in about 5% of children with ASD. The flavonoid luteolin inhibits human mast cells and microglia, as well as mTOR activation. Luteolin also inhibited the maternal activation (MIA) mouse model of autism and significantly improved communication and sociability, along with reduction of high serum levels of IL-6 and TNF, in a subgroup of children with ASD. The novel related flavonoid methoxyluteolin is a more potent inhibitor of both mast cells and microglia, as well as mTOR, than luteolin, is absorbed better and is tolerated by those with phenol intolerance and methylation defects. An intranasal formulation of methoxyluteolin that could deliver it directly to the brain through the cribriform plexus is under development [(Patents US 8,268,365 (09/18/12); US 9,050,275 (06/09/15); US 9,176,146 (11/03/15) awarded to TCT].

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