Abstract
Autism spectrum disorders (ASD) are characterized by deficits in sociability and communication, as well as severe anxiety and stereotypic movements. Moreover, over 50 % of children with ASD experience atopic symptoms indicative of mast cell (MC) activation (asthma, eczema, food allergies and/or intolerance) which correlate with the presence of brain auto-antibodies. ASD pathogenesis is unknown preventing the development of effective treatments. As a result, more than 70 % of children with ASD are prescribed psychopharmacologic agents that often have little benefit and serious adverse effects. Increasing evidence indicates that local brain inflammation is involved in ASD. In particular, there is activation and proliferation of microglia, which communicate with MCs, located perivascularly primarily in the thalamus and hypothalamus, as well as the lining of the ventricles. MCs are stimulated by corticotropin-releasing hormone (CRH) and neurotensin (NT) secreted from the hypothalamus under stress; these peptides can also induce each other’s surface receptors leading to autocrine and paracrine effects. Stimulated MCs release inflammatory and neurotoxic mediators that disrupt the blood-brain barrier (BBB), activate microglia and cause focal inflammation. CRH and NT are significantly increased in serum of ASD children compared to normotypic controls. Addressing the “allergic” and anxiety symptoms would not only improve the health of the patients, but could also potentially reduce the core symptoms of ASD. Use of the natural anti-inflammatory flavonoid luteolin, in an olive fruit oil preparation to increase oral absorption, appears to provide significant benefit and should be investigated further. Treatment approaches targeting brain inflammation could have a great benefit.
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References
Abdallah MW, Larsen N, Grove J, Norgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM (2012) Amniotic fluid chemokines and autism spectrum disorders: an exploratory study utilizing a Danish Historic Birth Cohort. Brain Behav Immun 26:170–176
Abdulla A, Zhao X, Yang F (2013) Natural polyphenols inhibit lysine-specific demethylase-1. J Biochem Pharmacol Res 1:56–63
Abraham SN, St John AL (2010) Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol 10:440–452
Adams JB, Audhya T, Donough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W (2011) Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatr 11:111
Aldinger KA, Plummer JT, Qiu S, Levitt P (2011) SnapShot: genetics of autism. Neuron 72:418
Alevizos M, Karagkouni A, Vasiadi M, Sismanopoulos N, Makris M, Kalogeromitros D, TheoharidesTC (2013) Rupatadine inhibits inflammatory mediator release from human LAD2 cultured mast cells stimulated by PAF.Ann Allergy Asthma Immunol 111:524–527
Alstadhaug KB (2014) Histamine in migraine and brain. Headache 54:246–259
Anagnostou E, Soorya L, Brian J, Dupuis A, Mankad D, Smile S, Jacob S (2014) Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth. Brain Res 1580:188–198
Angelidou A, Francis K, Vasiadi M, Alysandratos K-D, Zhang B, Theoharides A, Lykouras L, Kalogeromitros D, Theoharides T (2010) Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflam 7:48
Angelidou A, Alysandratos KD, Asadi S, Zhang B, Francis K, Vasiadi M, Kalogeromitros D, Theoharides TC (2011) Brief report: "allergic symptoms" in children with autism spectrum disorders. More than meets the eye? J Autism Dev Disord 41:1579–1585
Angelidou A, Asadi S, Alysandratos KD, Karagkouni A, Kourembanas S, Theoharides TC (2012) Perinatal stress, brain inflammation and risk of autism-review and proposal. BMC Pediatr 12:89
Antonelli T, Ferraro L, Fuxe K, Finetti S, Fournier J, Tanganelli S, De MM, Tomasini MC (2004) Neurotensin enhances endogenous extracellular glutamate levels in primary cultures of rat cortical neurons: involvement of neurotensin receptor in NMDA induced excitotoxicity. Cereb Cortex 14:466–473
Asadi S, Theoharides TC (2012) Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release, which is inhibited by luteolin. J Neuroinflam 9:85
Asadi S, Zhang B, Weng Z, Angelidou A, Kempuraj D, Alysandratos KD, Theoharides TC (2010) Luteolin and thiosalicylate inhibit HgCl(2) and thimerosal-induced VEGF release from human mast cells. Int J Immunopathol Pharmacol 23:1015–1020
Ashwood P, Van de Water J (2004) Is autism an autoimmune disease? Autoimmun Rev 3:557–562
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de WJ (2011) Altered T cell responses in children with autism. Brain Behav Immun 25:840–849
Bakermans-Kranenburg MJ, van IJM (2013) Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl. Psychiatry 3:e258
Banuelos-Cabrera I, Valle-Dorado MG, Aldana BI, Orozco-Suarez SA, Rocha L (2014) Role of histaminergic system in blood-brain barrier dysfunction associated with neurological disorders. Arch Med Res 45:677–686
Baptista FI, Henriques AG, Silva AM, Wiltfang J, da Cruz e Silva OA (2014) Flavonoids as therapeutic compounds targeting key proteins involved in Alzheimer’s disease. ACS Chem Neurosci 5:83–92
Barreau F, Salvador-Cartier C, Houdeau E, Bueno L, Fioramonti J (2008) Long-term alterations of colonic nerve-mast cell interactions induced by neonatal maternal deprivation in rats. Gut 57:582–590
Beaudet AL (2012) Neuroscience. Preventable forms of autism? Science 338:342–343
Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC, Steiner J, Connor TJ, Harkin A, Versnel MA, Drexhage HA (2012) The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 92:959–975
Beversdorf DQ, Manning SE, Hillier A, Anderson SL, Nordgren RE, Walters SE, Nagaraja HN, Cooley WC, Gaelic SE, Bauman ML (2005) Timing of prenatal stressors and autism. J Autism DevDisord 35:471–478
Blank U, Rivera J (2004) The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol 25:266–273
Blenner S, Reddy A, Augustyn M (2011) Diagnosis and management of autism in childhood. BMJ 343:d6238
Boudouda HB, Zeghib A, Karioti A, Bilia AR, Ozturk M, Aouni M, Kabouche A, Kabouche Z (2015) Antibacterial, antioxidant, anti-cholinesterase potential and flavonol glycosides of Biscutella raphanifolia (Brassicaceae). Pak J Pharm Sci 28:153–158
Braunschweig D, Van de Water J (2012) Maternal autoantibodies in autism. Arch Neurol 69:693–699
Broadstock M, Doughty C, Eggleston M (2007) Systematic review of the effectiveness of pharmacological treatments for adolescents and adults with autism spectrum disorder. Autism 11:335–348
Bryniarski K, Ptak W, Jayakumar A, Pullmann K, Caplan MJ, Chairoungdua A, Lu J, Adams BD, Sikora E, Nazimek K, Marquez S, Kleinstein SH, Sangwung P, Iwakiri Y, Delgato E, Redegeld F, Blokhuis BR, Wojcikowski J, Daniel AW, Groot KT, Askenase PW (2013) Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity. J Allergy Clin Immunol 132:170–181
Buescher AV, Cidav Z, Knapp M, Mandell DS (2014) Costs of autism spectrum disorders in the United kingdom and the United States. JAMA Pediatr 168:721–728
Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, Cetrulo CL, Theoharides TC (2005) Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol 174:7665–7675
Chakraborty S, Kaushik DK, Gupta M, Basu A (2010) Inflammasome signaling at the heart of central nervous system pathology. J Neurosci Res 88:1615–1631
Chen Z, Trapp BD (2015) Microglia and neuroprotection., J Neurochem
Chen HQ, Jin ZY, Wang XJ, Xu XM, Deng L, Zhao JW (2008) Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation. Neurosci Lett 448:175–179
Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, Pan TL, Bai YM (2014a) Is atopy in early childhood a risk factor for ADHD and ASD? a longitudinal study. J Psychosom Res 77:316–321
Chen Z, Zheng S, Li L, Jiang H (2014b) Metabolism of flavonoids in human: a comprehensive review. Curr Drug Metab 15:48–61
Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M (2007) Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 36:361–365
Ching H, Pringsheim T (2012) Aripiprazole for autism spectrum disorders (ASD). Cochrane Database Syst Rev 5, CD009043
Cocchiara R, Albeggiani G, Lampiasi N, Bongiovanni A, Azzolina A, Geraci D (1999) Histamine and tumor necrosis factor-a production from purified rat brain mast cells mediated by substance P. Neuroreport 10:575–578
Corcoran MP, McKay DL, Blumberg JB (2012) Flavonoid basics: chemistry, sources, mechanisms of action, and safety. J Nutr Gerontol Geriatr 31:176–189
Dahlgren J, Samuelsson AM, Jansson T, Holmang A (2006) Interleukin-6 in the maternal circulation reaches the rat fetus in mid-gestation. Pediatr Res 60:147–151
de Theije CG, Wu J, Koelink PJ, Korte-Bouws GA, Borre Y, Kas MJ, da Lopes SS, Korte SM, Olivier B, Garssen J, Kraneveld AD (2014) Autistic-like behavioural and neurochemical changes in a mouse model of food allergy. Behav Brain Res 261:265–274
Delong G (2011) A positive association found between autism prevalence and childhood vaccination uptake across the U.S. population. J Toxicol Environ Health A 74:903–916
Derecki NC, Privman E, Kipnis J (2010) Rett syndrome and other autism spectrum disorders--brain diseases of immune malfunction ? Mol Psychiatry 15:355–363
Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M (2008) How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. NeuroToxicol 29:190–201
Developmental Disabilities Monitoring Network Surveillance Year (2010) Principal InvestigatorsCenters for Disease Control and Prevention (CDC) (2014) Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ 63:1–21
Dickerson AS, Rahbar MH, Han I, Bakian AV, Bilder DA, Harrington RA, Pettygrove S, Durkin M, Kirby RS, Wingate MS, Tian LH, Zahorodny WM, Pearson DA, Moye LA III, Baio J (2015) Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury. Sci Total Environ 536:245–251
Dirscherl K, Karlstetter M, Ebert S, Kraus D, Hlawatsch J, Walczak Y, Moehle C, Fuchshofer R, Langmann T (2010) Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation 7:3
Donelan J, Boucher W, Papadopoulou N, Lytinas M, Papaliodis D, Theoharides TC (2006) Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc Natl Acad Sci U S A 103:7759–7764
Ecker C, Spooren W, Murphy D (2013) Developing new pharmacotherapies for autism. J Intern Med 274:308–320
Enoksson M, Lyberg K, Moller-Westerberg C, Fallon PG, Nilsson G, Lunderius-Andersson C (2011) Mast cells as sensors of cell injury through IL-33 recognition. J Immunol 186:2523–2528
Esposito P, Gheorghe D, Kandere K, Pang X, Conally R, Jacobson S, Theoharides TC (2001) Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res 888:117–127
Esposito P, Chandler N, Kandere-Grzybowska K, Basu S, Jacobson S, Connolly R, Tutor D, Theoharides TC (2002) Corticotropin-releasing hormone (CRH) and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther 303:1061–1066
Farr SA, Price TO, Dominguez LJ, Motisi A, Saiano F, Niehoff ML, Morley JE, Banks WA, Ercal N, Barbagallo M (2012) Extra virgin olive oil improves learning and memory in SAMP8 mice. J Alzheimers Dis 28:81–92
Fatokun AA, Liu JO, Dawson VL, Dawson TM (2013) Identification through high-throughput screening of 4'-methoxyflavone and 3',4'-dimethoxyflavone as novel neuroprotective inhibitors of parthanatos. Br J Pharmacol 169:1263–1278
Fido A, Al-Saad S (2005) Toxic trace elements in the hair of children with autism. Autism 9:290–298
Fombonne E (2009) Epidemiology of pervasive developmental disorders. Pediatr Res 65:591–598
Franco JL, Posser T, Missau F, Pizzolatti MG, Dos Santos AR, Souza DO, Aschner M, Rocha JB, Dafre AL, Farina M (2010) Structure-activity relationship of flavonoids derived from medicinal plants in preventing methylmercury-induced mitochondrial dysfunction. Environ Toxicol Pharmacol 30:272–278
Frisch M, Simonsen J (2015) Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark. J R Soc Med 108:266–279
Frye RE, Rossignol D, Casanova MF, Brown GL, Martin V, Edelson S, Coben R, Lewine J, Slattery JC, Lau C, Hardy P, Fatemi SH, Folsom TD, Macfabe D, Adams JB (2013) A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel. Front Public Health 1:31
Fu X, Zhang J, Guo L, Xu Y, Sun L, Wang S, Feng Y, Gou L, Zhang L, Liu Y (2014) Protective role of luteolin against cognitive dysfunction induced by chronic cerebral hypoperfusion in rats. Pharmacol Biochem Behav 126:122–130
Galli SJ, Grimbaldeston M, Tsai M (2008) Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 8:478–486
Geier DA, Kern JK, King PG, Sykes LK, Geier MR (2012) Hair toxic metal concentrations and autism spectrum disorder severity in young children. Int J Environ Res Public Health 9:4486–4497
Genuneit J, Braig S, Brandt S, Wabitsch M, Florath I, Brenner H, Rothenbacher D (2014) Infant atopic eczema and subsequent attention-deficit/hyperactivity disorder - A prospective birth cohort study. Pediatr Allergy Immunol 25:51–56
Ghanizadeh A (2010) Targeting neurotensin as a potential novel approach for the treatment of autism. J Neuroinflammation 7:58
Ghosh A, Michalon A, Lindemann L, Fontoura P, Santarelli L (2013) Drug discovery for autism spectrum disorder: challenges and opportunities. Nat Rev Drug Discov 12:777–790
Gillott A, Standen PJ (2007) Levels of anxiety and sources of stress in adults with autism. J Intellect Disabil 11:359–370
Goedert M, Lightman SL, Mantyh PW, Hunt SP, Emson PC (1985) Neurotensin-like immunoreactivity and neurotensin receptors in the rat hypothalamus and in the neurointermediate lobe of the pituitary gland. Brain Res 358:59–69
Gonzalez-Correa JA, Navas MD, Lopez-Villodres JA, Trujillo M, Espartero JL, De La Cruz JP (2008) Neuroprotective effect of hydroxytyrosol and hydroxytyrosol acetate in rat brain slices subjected to hypoxia-reoxygenation. Neurosci Lett 446:143–146
Gordon WA, Cantor JB, Johanning E, Charatz HJ, Ashman TA, Breeze JL, Haddad L, Abramowitz S (2004) Cognitive impairment associated with toxigenic fungal exposure: a replication and extension of previous findings. Appl Neuropsychol 11:65–74
Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML (2013) Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr 167:959–966
Grosso C, Valentao P, Ferreres F, Andrade PB (2013) The use of flavonoids in central nervous system disorders. Curr Med Chem 20:4697–4719
Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J, West AB, Arking DE (2014) Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 5:5748
Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88:1183–1241
Hagberg H, Gressens P, Mallard C (2012) Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol 71:444–457
Hagedorn M, Carter VL, Leong JC, Kleinhans FW (2010) Physiology and cryosensitivity of coral endosymbiotic algae (Symbiodinium). Cryobiology 60:147–158
Hanrahan JR, Chebib M, Johnston GA (2011) Flavonoid modulation of GABA(A) receptors. Br J Pharmacol 163:234–245
Harwood M, nielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC (2007) A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 45:2179–2205
Heilbrun LP, Palmer RF, Jaen CR, Svoboda MD, Miller CS, Perkins J (2015) Maternal chemical and drug intolerances: potential risk factors for autism and Attention Deficit Hyperactivity Disorder (ADHD). J Am Board Fam Med 28:461–470
Hendren RL (2013) Autism: biomedical complementary treatment approaches. Child Adolesc Psychiatr Clin N Am 22(443-56):vi
Herbert MR (2010) Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 23:103–110
Ho L, Ferruzzi MG, Janle EM, Wang J, Gong B, Chen TY, Lobo J, Cooper B, Wu QL, Talcott ST, Percival SS, Simon JE, Pasinetti GM (2013) Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer’s disease. FASEB J 27:769–781
Hollman PC, Katan MB (1997) Absorption, metabolism and health effects of dietary flavonoids in man. Biomed Pharmacother 51:305–310
Hollman PC, de Vries JH, van Leeuwen SD, Mengelers MJ, Katan MB (1995) Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am J Clin Nutr 62:1276–1282
Hollocks MJ, Howlin P, Papadopoulos AS, Khondoker M, Simonoff E (2014) Differences in HPA-axis and heart rate responsiveness to psychosocial stress in children with autism spectrum disorders with and without co-morbid anxiety. Psychoneuroendocrinology 46:32–45
Hosenbocus S, Chahal R (2013) Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 22:166–171
Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A 109:12776–12781
Huang M, Pang X, Karalis K, Theoharides TC (2003) Stress-induced interleukin-6 release in mice is mast cell-dependent and more pronounced in Apolipoprotein E knockout mice. Cardiovasc Res 59:241–249
Jager AK, Saaby L (2011) Flavonoids and the CNS. Molecules 16:1471–1485
Jang S, Kelley KW, Johnson RW (2008) Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci U S A 105:7534–7539
Jang S, Dilger RN, Johnson RW (2010a) Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J Nutr 140:1892–1898
Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K (2010b) A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A 107:2687–2692
Jedrychowski W, Maugeri U, Perera F, Stigter L, Jankowski J, Butscher M, Mroz E, Flak E, Skarupa A, Sowa A (2011) Cognitive function of 6-year old children exposed to mold-contaminated homes in early postnatal period. Prospective birth cohort study in Poland. Physiol Behav 104:989–995
Johnson RA, Lam M, Punzo AM, Li H, Lin BR, Ye K, Mitchell GS, Chang Q (2012) 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome. J Appl Physiol 112:704–710
Jones KA, Thomsen C (2013) The role of the innate immune system in psychiatric disorders. Mol Cell Neurosci 53:52–62
Jones QR, Warford J, Rupasinghe HP, Robertson GS (2012) Target-based selection of flavonoids for neurodegenerative disorders. Trends Pharmacol Sci 33:602–610
Jyonouchi H (2010) Autism spectrum disorders and allergy: observation from a pediatric allergy/immunology clinic. Expert Rev Clin Immunol 6:397–411
Jyonouchi H, Sun S, Le H (2001) Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 120:170–179
Jyonouchi H, Sun S, Itokazu N (2002) Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology 46:76–84
Kalesnikoff J, Galli SJ (2008) New developments in mast cell biology. Nat Immunol 9:1215–1223
Kalogeromitros D, Syrigou EI, Makris M, Kempuraj D, Stavrianeas NG, Vasiadi M, Theoharides TC (2007) Nasal provocation of patients with allergic rhinitis and the hypothalamic-pituitary-adrenal axis. Annals Allergy, Asthma, Immunology 98:269–273
Kandere-Grzybowska K, Letourneau R, Kempuraj D, Donelan J, Poplawski S, Boucher W, Athanassiou A, Theoharides TC (2003) IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J Immunol 171:4830–4836
Kao TK, Ou YC, Lin SY, Pan HC, Song PJ, Raung SL, Lai CY, Liao SL, Lu HC, Chen CJ (2011) Luteolin inhibits cytokine expression in endotoxin/cytokine-stimulated microglia. J Nutr Biochem 22:612–624
Karagkouni A, Alevizos M, Theoharides TC (2013) Effect of stress on brain inflammation and multiple sclerosis. Autoimmun Rev 12:947–953
Kawanishi S, Oikawa S, Murata M (2005) Evaluation for safety of antioxidant chemopreventive agents. Antioxid Redox Signal 7:1728–1739
Kawikova I, Askenase PW (2014) Diagnostic and therapeutic potentials of exosomes in CNS diseases. Brain Res 1617:63–71
Kempuraj D, Papadopoulou NG, Lytinas M, Huang M, Kandere-Grzybowska K, Madhappan B, Boucher W, Christodoulou S, Athanassiou A, Theoharides TC (2004) Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells. Endocrinology 145:43–48
Kempuraj D, Madhappan B, Christodoulou S, Boucher W, Cao J, Papadopoulou N, Cetrulo CL, Theoharides TC (2005) Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells. Br J Pharmacol 145:934–944
Kempuraj D, Tagen M, Iliopoulou BP, Clemons A, Vasiadi M, Boucher W, House M, Wolferg A, Theoharides TC (2008) Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell dependent stimulation of Jurkat T cells. Br J Pharmacol 155:1076–1084
Kempuraj D, Asadi S, Zhang B, Manola A, Hogan J, Peterson E, Theoharides TC (2010) Mercury induces inflammatory mediator release from human mast cells. J Neuroinflammation 7:20
Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H (2000) Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy 30:501–508
King BH, Hollander E, Sikich L, McCracken JT, Scahill L, Bregman JD, Donnelly CL, Anagnostou E, Dukes K, Sullivan L, Hirtz D, Wagner A, Ritz L (2009) Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism. Arch Gen Psychiatry 66:583–590
Kogan MD, Blumberg SJ, Schieve LA, Boyle CA, Perrin JM, Ghandour RM, Singh GK, Strickland BB, Trevathan E, van Dyck PC (2009) Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics 5:1395–1403
Kritas SK, Caraffa A, Antinolfi P, Saggini A, Pantalone A, Rosati M, Tei M, Speziali A, Saggini R, Pandolfi F, Cerulli G, Conti P (2014a) Nerve growth factor interactions with mast cells. Int J Immunopathol Pharmacol 27:15–19
Kritas SK, Saggini A, Cerulli G, Caraffa A, Antinolfi P, Pantalone A, Rosati M, Tei M, Speziali A, Saggini R, Conti P (2014b) Corticotropin-releasing hormone, microglia and mental disorders. Int J Immunopathol Pharmacol 27:163–167
Kumar A, Goyal R (2008) Quercetin protects against acute immobilization stress-induced behaviors and biochemical alterations in mice. J Med Food 11:469–473
Kushki A, Drumm E, Pla MM, Tanel N, Dupuis A, Chau T, Anagnostou E (2013) Investigating the autonomic nervous system response to anxiety in children with autism spectrum disorders. PLoS One 8, e59730
Lai MC, Lombardo MV, Baron-Cohen S (2014) Autism. Lancet 383:896–910
Lake JK, Weiss JA, Dergal J, Lunsky Y (2014) Child, parent, and service predictors of psychotropic polypharmacy among adolescents and young adults with an autism spectrum disorder. J Child Adolesc Psychopharmacol 24:486–493
Lanni KE, Schupp CW, Simon D, Corbett BA (2012) Verbal ability, social stress, and anxiety in children with autistic disorder. Autism 16:123–138
Leigh JP, Du J (2015) Brief report: forecasting the economic burden of Autism in 2015 and 2025 in the United States. J Autism Dev, Disord
Li W, Sperry JB, Crowe A, Trojanowski JQ, Smith AB III, Lee VM (2009a) Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau. J Neurochem 110:1339–1351
Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M (2009b) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207:111–116
Lin TY, Lu CW, Chang CC, Huang SK, Wang SJ (2011) Luteolin inhibits the release of glutamate in rat cerebrocortical nerve terminals. J Agric Food Chem 59:8458–8466
Liu R, Gao M, Qiang GF, Zhang TT, Lan X, Ying J, Du GH (2009) The anti-amnesic effects of luteolin against amyloid beta(25-35) peptide-induced toxicity in mice involve the protection of neurovascular unit. Neuroscience 162:1232–1243
Liu R, Zhang TT, Zhou D, Bai XY, Zhou WL, Huang C, Song JK, Meng FR, Wu CX, Li L, Du GH (2013a) Quercetin protects against the Abeta(25-35)-induced amnesic injury: involvement of inactivation of rage-mediated pathway and conservation of the NVU. Neuropharmacology 67:419–431
Liu Y, Tian X, Gou L, Sun L, Ling X, Yin X (2013b) Luteolin attenuates diabetes-associated cognitive decline in rats. Brain Res Bull 94C:23–29
Liu Y, Fu X, Lan N, Li S, Zhang J, Wang S, Li C, Shang Y, Huang T, Zhang L (2014) Luteolin protects against high fat diet-induced cognitive deficits in obesity mice. Behav Brain Res 267:178–188
Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, Lekeux P, Coban C, Akira S, Ishii KJ, Bureau F, Desmet CJ (2011) DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med 17:996–1002
Marti LF (2014) Dietary interventions in children with autism spectrum disorders—an updated review of the research evidence. Curr Clin Pharmacol 9:335–349
Martin S, Vincent JP, Mazella J (2003) Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J Neurosci 23:1198–1205
Martinez-Lapiscina EH, Clavero P, Toledo E, San JB, Sanchez-Tainta A, Corella D, Lamuela-Raventos RM, Martinez JA, Martinez-Gonzalez MA (2013) Virgin olive oil supplementation and long-term cognition: the PREDIMED-NAVARRA randomized, trial. J Nutr Health Aging 17:544–552
Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D, Keefer A, Murray DS, Freedman B, Lowery LA (2013) Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol 41:165–176
McKee AS, Burchill MA, Munks MW, Jin L, Kappler JW, Friedman RS, Jacobelli J, Marrack P (2013) Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. Proc Natl Acad Sci U S A 110:E1122–E1131
McKittrick CM, Lawrence CE, Carswell HV (2015) Mast cells promote blood brain barrier breakdown and neutrophil infiltration in a mouse model of focal cerebral ischemia. J Cereb Blood Flow Metab 35:638–647
Mecocci P, Tinarelli C, Schulz RJ, Polidori MC (2014) Nutraceuticals in cognitive impairment and Alzheimer’s disease. Front Pharmacol 5:147
Middleton EJ, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev 52:673–751
Miller LG, Lee-Parritz A, Greenblatt DJ, Theoharides TC (1988) High affinity benzodiazepine receptors on rat peritoneal mast cells and RBL-1 cells: binding characteristics and effects on granule secretion. Pharmacology 36:52–60
Mohagheghi F, Bigdeli MR, Rasoulian B, Zeinanloo AA, Khoshbaten A (2010) Dietary virgin olive oil reduces blood brain barrier permeability, brain edema, and brain injury in rats subjected to ischemia-reperfusion. ScientificWorldJournal 10:1180–1191
Mohagheghi F, Bigdeli MR, Rasoulian B, Hashemi P, Pour MR (2011) The neuroprotective effect of olive leaf extract is related to improved blood-brain barrier permeability and brain edema in rat with experimental focal cerebral ischemia. Phytomedicine 18:170–175
Mohiuddin S, Ghaziuddin M (2013) Psychopharmacology of autism spectrum disorders: a selective review. Autism 17:645–654
Mohr DC, Goodkin DE, Bacchetti P, Boudewyn AC, Huang L, Marrietta P, Cheuk W, Dee B (2000) Psychological stress and the subsequent appearances of new brain MRI lesions in MS. Neurology 55:55–61
Molteni M, Nobile M, Cattaneo D, Radice S, Clementi E (2014) Potential benefits and limits of psychopharmacological therapies in pervasive developmental disorders. Curr Clin Pharmacol 9:365–376
Morgan JT, Chana G, Abramson I, Semendeferi K, Courchesne E, Everall IP (2012) Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res 1456:72–81
Mostafa GA, Al-Ayadhi LY (2013) The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children. J Neuroimmunol 261:77–81
Moussion C, Ortega N, Girard JP (2008) The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One 3, e3331
Mullol J, Bousquet J, Bachert C, Canonica GW, Gimenez-Arnau A, Kowalski ML, Simons FE, Maurer M, Ryan D, Scadding G (2015) Update on rupatadine in the management of allergic disorders. Allergy 70(Suppl 100):1–24
Munkholm K, Vinberg M, Vedel KL (2013) Cytokines in bipolar disorder: a systematic review and meta-analysis. J Affect Disord 144:16–27
Mustain WC, Rychahou PG, Evers BM (2011) The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrinol Diabetes Obes 18:75–82
Naik US, Gangadharan C, Abbagani K, Nagalla B, Dasari N, Manna SK (2011) A study of nuclear transcription factor-kappa B in childhood autism. PLoS One 6, e19488
Nakae S, Suto H, Iikura M, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2006) Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 176:2238–2248
Nakae S, Suto H, Berry GJ, Galli SJ (2007) Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice. Blood 109:3640–3648
Ohnmacht C, Voehringer D (2010) Basophils protect against reinfection with hookworms independently of mast cells and memory Th2 cells. J Immunol 184:344–350
Olfson M, Druss BG, Marcus SC (2015) Trends in mental health care among children and adolescents. N Engl J Med 372:2029–2038
Olszewski MB, Groot AJ, Dastych J, Knol EF (2007) TNF trafficking to human mast cell granules: mature chain-dependent endocytosis. J Immunol 178:5701–5709
Onore C, Careaga M, Ashwood P (2012) The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 26:383–392
Pang X, Letourneau R, Rozniecki JJ, Wang L, Theoharides TC (1996) Definitive characterization of rat hypothalamic mast cells. Neuroscience 73:889–902
Parikh MS, Kolevzon A, Hollander E (2008) Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability. J Child Adolesc Psychopharmacol 18:157–178
Park HH, Lee S, Son HY, Park SB, Kim MS, Choi EJ, Singh TS, Ha JH, Lee MG, Kim JE, Hyun MC, Kwon TK, Kim YH, Kim SH (2008) Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res 31:1303–1311
Parker-Athill E, Luo D, Bailey A, Giunta B, Tian J, Shytle RD, Murphy T, Legradi G, Tan J (2009) Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J Neuroimmunol 217:20–27
Passamonti S, Terdoslavich M, Franca R, Vanzo A, Tramer F, Braidot E, Petrussa E, Vianello A (2009) Bioavailability of flavonoids: a review of their membrane transport and the function of bilitranslocase in animal and plant organisms. Curr Drug Metab 10:369–394
Pitt J, Roth W, Lacor P, Smith AB III, Blankenship M, Velasco P, De FF, Breslin P, Klein WL (2009) Alzheimer’s-associated Abeta oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal. Toxicol Appl Pharmacol 240:189–197
Preti A, Melis M, Siddi S, Vellante M, Doneddu G, Fadda R (2014) Oxytocin and autism: a systematic review of randomized controlled trials. J Child Adolesc Psychopharmacol 24:54–68
Rais TB, Rais A (2014) Association between antidepressants use during pregnancy and autistic spectrum disorders: a meta-analysis. Innov Clin Neurosci 11:18–22
Regitz C, Dussling LM, Wenzel U (2014) Amyloid-beta (Abeta(1-42))-induced paralysis in Caenorhabditis elegans is inhibited by the polyphenol quercetin through activation of protein degradation pathways. Mol Nutr Food Res 58:1931–1940
Roberts AL, Koenen KC, Lyall K, Robinson EB, Weisskopf MG (2015) Association of autistic traits in adulthood with childhood abuse, interpersonal victimization, and posttraumatic stress. Child Abuse Negl 45:135–142
Rocha SM, Pires J, Esteves M, Graca B, Bernardino L (2014) Histamine: a new immunomodulatory player in the neuron-glia crosstalk. Front Cell Neurosci 8:120
Rodgers J, Glod M, Connolly B, McConachie H (2012) The relationship between anxiety and repetitive behaviours in autism spectrum disorder. J Autism Dev Disord 42:2404–2409
Rodgers AB, Morgan CP, Bronson SL, Revello S, Bale TL (2013) Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 33:9003–9012
Rodriguez JI, Kern JK (2011) Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol 7:205–213
Rogers SJ, Vismara LA (2008) Evidence-based comprehensive treatments for early autism. J Clin Child Adolesc Psychol 37:8–38
Ronald A, Pennell CE, Whitehouse AJ (2010) Prenatal maternal stress associated with ADHD and autistic traits in early childhood. Front Psychol 1:223
Rossi CC, Van de WJ, Rogers SJ, Amaral DG (2011) Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders. Brain Behav Immun 25:1123–1135
Rossignol DA, Frye RE (2012a) A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry 17:389–401
Rossignol DA, Frye RE (2012b) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 17:290–314
Rozniecki JJ, Dimitriadou V, Lambracht-Hall M, Pang X, Theoharides TC (1999) Morphological and functional demonstration of rat dura mast cell-neuron interactions in vitro and in vivo. Brain Res 849:1–15
rrode-Bruses G, Bruses JL (2012) Maternal immune activation by poly I:C induces expression of cytokines IL-1beta and IL-13, chemokine MCP-1 and colony stimulating factor VEGF in fetal mouse brain. J Neuroinflammation. 9:83
Rubartelli A, Lotze MT (2007) Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol 28:429–436
Ruhela RK, Prakash A, Medhi B (2015) An urgent need for experimental animal model of autism in drug development. Ann Neurosci 22:44–49
Sanders DS, Aziz I (2012) Non-celiac wheat sensitivity: separating the wheat from the chat! Am J Gastroenterol 107:1908–1912
Sandig H, Bulfone-Paus S (2012) TLR signaling in mast cells: common and unique features. Front Immunol 3:185
Sandin S, Schendel D, Magnusson P, Hultman C, Suren P, Susser E, Gronborg T, Gissler M, Gunnes N, Gross R, Henning M, Bresnahan M, Sourander A, Hornig M, Carter K, Francis R, Parner E, Leonard H, Rosanoff M, Stoltenberg C, Reichenberg A (2015) Autism risk associated with parental age and with increasing difference in age between the parents., Mol. Psychiatry
Scattoni ML, Martire A, Cartocci G, Ferrante A, Ricceri L (2013) Reduced social interaction, behavioural flexibility and BDNF signalling in the BTBR T+ tf/J strain, a mouse model of autism. Behav Brain Res 251:35–40
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705
Schmidt BM, Ribnicky DM, Lipsky PE, Raskin I (2007) Revisiting the ancient concept of botanical therapeutics. Nat Chem Biol 3:360–366
Schoch C (2003) In vitro inhibition of human conjunctival mast-cell degranulation by ketotifen. J Ocul Pharmacol Ther 19:75–81
Schubart JR, Camacho F, Leslie D (2014) Psychotropic medication trends among children and adolescents with autism spectrum disorder in the Medicaid program. Autism 18:631–637
Seelinger G, Merfort I, Schempp CM (2008) Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med 74:1667–1677
Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, Donald-Smith GP, Gao H, Hennessy L, Finnerty CC, Lopez CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. PNAS 110:3507–3512
Shan L, Bao AM, Swaab DF (2015) The human histaminergic system in neuropsychiatric disorders. Trends Neurosci 38:167–177
Sharma V, Mishra M, Ghosh S, Tewari R, Basu A, Seth P, Sen E (2007) Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull 73:55–63
Sheikh IA, Ali R, Dar TA, Kamal MA (2012) An overview on potential neuroprotective compounds for management of Alzheimer’s disease. CNS Neurol Disord Drug Targets 11:1006–1011
Shim SY, Park JR, Byun DS (2012) 6-Methoxyluteolin from Chrysanthemum zawadskii var. latilobum suppresses histamine release and calcium influx via down-regulation of FcepsilonRI alpha chain expression. J Microbiol Biotechnol 22:622–627
Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, Zimmerman AW (2014) Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A 111:15550–15555
Skaper SD, Giusti P, Facci L (2012) Microglia and mast cells: two tracks on the road to neuroinflammation. FASEB J 26:3103–3117
Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702
Sochocky N, Milin R (2013) Second generation antipsychotics in Asperger’s Disorder and high functioning autism: a systematic review of the literature and effectiveness of meta-analysis. Curr Clin Pharmacol 8:370–379
Solanki I, Parihar P, Mansuri ML, Parihar MS (2015) Flavonoid-based therapies in the early management of neurodegenerative diseases. Adv Nutr 6:64–72
Spencer D, Marshall J, Post B, Kulakodlu M, Newschaffer C, Dennen T, Azocar F, Jain A (2013) Psychotropic medication use and polypharmacy in children with autism spectrum disorders. Pediatrics 132:833–840
Sternthal MJ, Enlow MB, Cohen S, Canner MJ, Staudenmayer J, Tsang K, Wright RJ (2009) Maternal interpersonal trauma and cord blood IgE levels in an inner-city cohort: a life-course perspective. J Allergy Clin Immunol 124:954–960
Takano T (2015) Role of microglia in Autism: recent advances. Dev Neurosci 37:195–202
Taliou A, Zintzaras E, Lykouras L, Francis K (2013) 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. Clin Ther 35:592–602
Theoharides TC (2009) Autism spectrum disorders and mastocytosis. Int J Immunopathol Pharmacol 22:859–865
Theoharides TC (2013) Is a subtype of autism “allergy of the brain”? Clin Ther 35:584–591
Theoharides TC, Asadi S (2012) Unwanted interactions among psychotropic drugs and other treatments for Autism Spectrum Disorders. J Clin Psychopharmacol 32:437–440
Theoharides TC, Cochrane DE (2004) Critical role of mast cells in inflammatory diseases and the effect of acute stress. J Neuroimmunol 146:1–12
Theoharides TC, Doyle R (2008) Autism, gut-blood-brain barrier and mast cells. J Clin Psychopharm 28:479–483
Theoharides TC, Konstantinidou A (2007) Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci 12:1615–1628
Theoharides TC, Zhang B (2011) Neuro-Inflammation, blood-brain barrier, seizures and autism. J Neuroinflammation 8:168
Theoharides TC, Spanos CP, Pang X, Alferes L, Ligris K, Letourneau R, Rozniecki JJ, Webster E, Chrousos G (1995) Stress-induced intracranial mast cell degranulation. A corticotropin releasing hormone-mediated effect. Endocrinology 136:5745–5750
Theoharides TC, Weinkauf C, Conti P (2004) Brain cytokines and neuropsychiatric disorders. J Clin Psychopharmacol 24:577–581
Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A (2005) The role of mast cells in migraine pathophysiology. Brain Res Brain Res Rev 49:65–76
Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 217:65–78
Theoharides TC, Doyle R, Francis K, Conti P, Kalogeromitros D (2008) Novel therapeutic targets for autism. Trends Pharmacol Sci 29:375–382
Theoharides TC, Kempuraj D, Redwood L (2009) Autism: an emerging ‘neuroimmune disorder’ in search of therapy. Exp Opin Pharmacotherapy 10:2127–2143
Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, Kalogeromitros D (2010a) Mast cells and inflammation. Biochim Biophys Acta 1822:21–33
Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, Kalogeromitros D (2010b) Mast cells and inflammation. Biochim Biophys Acta 1822:21–33
Theoharides TC, Zhang B, Kempuraj D, Tagen M, Vasiadi M, Angelidou A, Alysandratos KD, Kalogeromitros D, Asadi S, Stavrianeas N, Peterson E, Leeman S, Conti P (2010c) IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci U S A 107:4448–4453
Theoharides TC, Angelidou A, Alysandratos KD, Zhang B, Asadi S, Francis K, Toniato E, Kalogeromitros D (2012a) Mast cell activation and autism. Biochim Biophys Acta 1822:34–41
Theoharides TC, Asadi S, Panagiotidou S (2012b) A case series of a luteolin formulation (NeuroProtek(R)) in children with autism spectrum disorders. Int J Immunopathol Pharmacol 25:317–323
Theoharides TC, Asadi S, Panagiotidou S, Weng Z (2013a) The “missing link” in autoimmunity and autism: Extracellular mitochondrial components secreted from activated live mast cells. Autoimmun Rev 12:1136–1142
Theoharides TC, Asadi S, Patel AB (2013b) Focal brain inflammation and autism. J Neuroinflammation 10:46
Theoharides TC, Conti P, Economu M (2014) Brain inflammation, neuropsychiatric disorders, and immunoendocrine effects of luteolin. J Clin Psychopharmacol 34:187–189
Theoharides TC, Stewart JM, Hatziagelaki E, Kolaitis G (2015a) Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci 9:225
Theoharides TC, Stewart JM, Panagiotidou S, Melamed I (2015b) Mast cells, brain inflammation and autism., Eur J Pharmacol
Theoharides TC, Valent P, Akin C (2015c) Mast cells, mastocytosis, and related disorders. N Engl J Med 373:163–172
Theoharides TC, Valent P, Akin C (2015d) Mast cells, mastocytosis, and related disorders. N Engl J Med 373:163–172
Theoharides T, Athanassiou M, Panagiotidou S, Doyle R (2015e) Dysregulated brain immunity and neurotrophin signaling in Rett syndrome and autism spectrum disorders. J Neuroimmunol 279:33–38
Thilakarathna SH, Rupasinghe HP (2013) Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 5:3367–3387
Tomljenovic L, Shaw CA (2011) Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? J Inorg Biochem 105:1489–1499
Tonhajzerova I, Ondrejka I, Mestanik M, Mikolka P, Hrtanek I, Mestanikova A, Bujnakova I, Mokra D (2015) Inflammatory activity in autism spectrum disorder., Adv Exp Med Biol
Trivedi MS, Deth RC (2012) Role of a redox-based methylation switch in mRNA life cycle (pre- and post-transcriptional maturation) and protein turnover: implications in neurological disorders. Front Neurosci 6:92
Tsai FS, Peng WH, Wang WH, Wu CR, Hsieh CC, Lin YT, Feng IC, Hsieh MT (2007) Effects of luteolin on learning acquisition in rats: involvement of the central cholinergic system. Life Sci 80:1692–1698
Tsai JD, Chang SN, Mou CH, Sung FC, Lue KH (2013) Association between atopic diseases and attention-deficit/hyperactivity disorder in childhood: a population-based case-control study. Ann Epidemiol 23:185–188
Tsilioni I, Dodman N, Petra AI, Taliou A, Francis K, Moon-Fanelli AA, Shuster L, Theoharides TC (2014a) Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing bull terriers with a phenotype similar to autism. Transl Psychiatry 4, e466
Tsilioni I, Panagiotidou S, Theoharides TC (2014b) Exosomes in neurologic and psychiatric disorders. Clin Ther 36:882–888
Tsilioni I, Taliou A, Francis K, Theoharides TC (2015) Children with autism spectrum disorders, who improved with a luteolin containing dietary formulation, show reduced serum levels of TNF and IL-6. Transl Psychiatry 5, e647
Valicenti-McDermott M, Burrows B, Bernstein L, Hottinger K, Lawson K, Seijo R, Schechtman M, Shulman L, Shinnar S (2014) Use of complementary and alternative medicine in children with autism and other developmental disabilities: associations with ethnicity, child comorbid symptoms, and parental stress. J Child Neurol 29:360–367
van Steensel FJ, Bogels SM, Perrin S (2011) Anxiety disorders in children and adolescents with autistic spectrum disorders: a meta-analysis. Clin Child Fam Psychol Rev 14:302–317
Vanuytsel T, van WS, Vanheel H, Vanormelingen C, Verschueren S, Houben E, Salim RS, Toth J, Holvoet L, Farre R, Van OL, Boeckxstaens G, Verbeke K, Tack J (2014) Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut 63:1293–1299
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57:67–81
Vasa RA, Mazurek MO (2015) An update on anxiety in youth with autism spectrum disorders. Curr Opin Psychiatry 28:83–90
Vasiadi M, Kalogeromitros D, Kempuraj D, Clemons A, Zhang B, Chliva C, Makris M, Wolfberg A, House M, Theoharides TC (2010) Rupatadine inhibits proinflammatory mediator secretion from human mast cells triggered by different stimuli. Int. Arch. Allergy Immunol 151:38–45
Vauzour D (2014) Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer’s disease pathophysiology. J Sci Food Agric 94:1042–1056
Verbeek R, Plomp AC, van Tol EA, van Noort JM (2004) The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells. Biochem Pharmacol 68:621–629
Volkmar FR (2009) Citalopram treatment in children with autism spectrum disorders and high levels of repetitive behavior. Arch Gen Psychiatry 66:581–582
Walle T (2007) Methylation of dietary flavones greatly improves their hepatic metabolic stability and intestinal absorption. Mol Pharm 4:826–832
Wang W, Ji P, Riopelle RJ, Dow KE (2002) Functional expression of corticotropin-releasing hormone (CRH) receptor 1 in cultured rat microglia. J Neurochem 80:287–294
Wang DM, Li SQ, Wu WL, Zhu XY, Wang Y, Yuan HY (2014) Effects of long-term treatment with quercetin on cognition and mitochondrial function in a mouse model of Alzheimer’s disease. Neurochem Res 39:1533–1543
Wei G, Hwang L, Tsai C (2014) Absolute bioavailability, pharmacokinetics and excretion of 5,7,3',4' -tetramethoxyflavone in rats. J Functional Foods 7:136–141
Weisman O, Agerbo E, Carter CS, Harris JC, Uldbjerg N, Henriksen TB, Thygesen M, Mortensen PB, Leckman JF, Dalsgaard S (2015) Oxytocin-augmented labor and risk for autism in males. Behav Brain Res 284:207–212
Weng Z, Patel A, Panagiotidou S, Theoharidess TC (2014) The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J Allergy Clin Immunol 14:1044–1052
Williams K, Wheeler DM, Silove N, Hazell P (2010) Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev 8, CD004677
Williams K, Wray JA, Wheeler DM (2012) Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev 4, CD003495
Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral DG, Van de WJ (2009) Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun 23:64–74
Wong PH, White KM (2015) Impact of immunoglobulin therapy in pediatric disease: a review of immune mechanisms. Clin Rev Allergy Immunol
Wong AY, Hsia Y, Chan EW, Murphy DG, Simonoff E, Buitelaar JK, Wong IC (2014) The Variation of Psychopharmacological Prescription Rates for People With Autism Spectrum Disorder (ASD) in 30 Countries. Autism Res 7:543–554
Xu SL, Bi CW, Choi RC, Zhu KY, Miernisha A, Dong TT, Tsim KW (2013) Flavonoids induce the synthesis and secretion of neurotrophic factors in cultured rat astrocytes: a signaling response mediated by estrogen receptor. Evid Based Complement Alternat Med 2013:127075
Yaghmaie P, Koudelka CW, Simpson EL (2013) Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol 131:428–433
Yoo H (2015) Genetics of autism spectrum disorder: current status and possible clinical applications. Exp Neurobiol 24:257–272
Yoo DY, Choi JH, Kim W, Nam SM, Jung HY, Kim JH, Won MH, Yoon YS, Hwang IK (2013) Effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia model. Neurol Res 35:813–820
Young NJ, Findling RL (2015) An update on pharmacotherapy for autism spectrum disorder in children and adolescents. Curr Opin Psychiatry 28:91–101
Yui K, Koshiba M, Nakamura S, Kobayashi Y (2012) Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in individuals with autism spectrum disorders: a double-blind, placebo-controlled, randomized trial. J Clin Psychopharmacol 32:200–206
Zaidan H, Leshem M, Gaisler-Salomon I (2013) Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring. Biol Psychiatry 74:680–687
Zerbo O, Yoshida C, Grether JK, Van de WJ, Ashwood P, Delorenze GN, Hansen RL, Kharrazi M, Croen LA (2014) Neonatal cytokines and Chemokines and risk of autism spectrum disorder: the early markers for autism (EMA) study: a case-control study. J Neuroinflammation 11:113
Zerbo O, Leong A, Barcellos L, Bernal P, Fireman B, Croen LA (2015) Immune mediated conditions in autism spectrum disorders. Brain Behav Immun 46:232–236
Zhang B, Angelidou A, Alysandratos KD, Vasiadi M, Francis K, Asadi S, Theoharides A, Sideri K, Lykouras L, Kalogeromitros D, Theoharides TC (2010) Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J Neuroinflammation 7:80
Zhang B, Alysandratos KD, Angelidou A, Asadi S, Sismanopoulos N, Delivanis DA, Weng Z, Miniati A, Vasiadi M, Katsarou-Katsari A, Miao B, Leeman SE, Kalogeromitros D, Theoharides TC (2011) Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: Relevance to atopic dermatitis. J Allergy Clin Immunol 127:1522–1531
Zhang B, Asadi S, Weng Z, Sismanopoulos N, Theoharides TC (2012a) Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions. PloS One 7, e49767
Zhang B, Weng Z, Sismanopoulos N, Asadi S, Therianou A, Alysandratos KD, Angelidou A, Shirihai O, Theoharides TC (2012b) Mitochondria distinguish granule-stored from de novo synthesized tumor necrosis factor secretion in human mast cells. Int Arch. Allergy Immunol 159:23–32
Zhang S, Zeng X, Yang H, Hu G, He S (2012c) Mast cell tryptase induces microglia activation via protease-activated receptor 2 signaling. Cell Physiol Biochem 29:931–940
Zhu LH, Bi W, Qi RB, Wang HD, Lu DX (2011) Luteolin inhibits microglial inflammation and improves neuron survival against inflammation. Int J Neurosci 121:329–336
Zhu J, Qu C, Lu X, Zhang S (2014) Activation of microglia by histamine and substance P. Cell Physiol Biochem 34:768–780
Ziats MN, Rennert OM (2011) Expression profiling of autism candidate genes during human brain development implicates central immune signaling pathways. PLoS One 6, e24691
Zimmerman AW, Jyonouchi H, Comi AM, Connors SL, Milstien S, Varsou A, Heyes MP (2005) Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol 33:195–201
Acknowledgements
Aspects of the work discussed were funded in part by the Autism Research Institute, the National Autism Association, Safe Minds and The Jane Botsford Johnson Foundation.
Competing Interests
The authors declare they have no competing interests.
Disclosures
TCT has been awarded US Patents No 8,268,365; 9,050,275 and 9,176,146 covering the treatment of brain inflammation and ASD.
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Theoharides, T.C., Tsilioni, I. (2017). Autism Spectrum Disorders. In: Ikezu, T., Gendelman, H. (eds) Neuroimmune Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-44022-4_40
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DOI: https://doi.org/10.1007/978-3-319-44022-4_40
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