Focal brain inflammation and autism

  • Theoharis C Theoharides1, 3, 4, 5Email author,

    Affiliated with

    • Shahrzad Asadi1, 2 and

      Affiliated with

      • Arti B Patel1, 6

        Affiliated with

        Journal of Neuroinflammation201310:46

        DOI: 10.1186/1742-2094-10-46

        Received: 22 January 2013

        Accepted: 15 March 2013

        Published: 9 April 2013

        Abstract

        Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Autism spectrum disorders (ASD) are characterized by social and learning disabilities that affect as many as 1/80 children in the USA. There is still no definitive pathogenesis or reliable biomarkers for ASD, thus significantly curtailing the development of effective therapies. Many children with ASD regress at about age 3 years, often after a specific event such as reaction to vaccination, infection, stress or trauma implying some epigenetic triggers, and may constitute a distinct phenotype. ASD children respond disproportionally to stress and are also affected by food and skin allergies. Corticotropin-releasing hormone (CRH) is secreted under stress and together with neurotensin (NT) stimulates mast cells and microglia resulting in focal brain inflammation and neurotoxicity. NT is significantly increased in serum of ASD children along with mitochondrial DNA (mtDNA). NT stimulates mast cell secretion of mtDNA that is misconstrued as an innate pathogen triggering an auto-inflammatory response. The phosphatase and tensin homolog (PTEN) gene mutation, associated with the higher risk of ASD, which leads to hyper-active mammalian target of rapamycin (mTOR) signalling that is crucial for cellular homeostasis. CRH, NT and environmental triggers could hyperstimulate the already activated mTOR, as well as stimulate mast cell and microglia activation and proliferation. The natural flavonoid luteolin inhibits mTOR, mast cells and microglia and could have a significant benefit in ASD.

        Introduction

        Focal brain inflammation

        Increasing evidence indicates that brain inflammation is important in the pathogenesis of neuropsychiatric disorders [1, 2]. Autism spectrum disorders (ASD) are pervasive neuro-developmental disorders characterized by varying degrees of deficiencies in social interactions, intelligence, and language, as well as the presence of stereotypic behaviors [36]. Recent results from the Centers of Disease Control in the USA indicate that as many as 1/80 children have ASD [7]. Many such children regress at about age 3 years, often after a specific event such as reaction to vaccination, infection [8, 9], trauma [10, 11], toxic exposures [12] or stress [13], implying the importance of some environmental triggers [14, 15].

        Increasing evidence points to some immune dysfunction/inflammation in ASD [16, 17]. The markers of inflammation identified in the brain and cerebrospinal fluid (CSF) of many ASD patients include TNF, IL-6 and monocyte chemotactic protein 1 (MCP-1), the latter of which also is chemotactic for mast cells [18]. Pro-inflammatory cytokine mRNA (IL-1α, IL-1β, IL-6 and TNF-α) is increased in brain inflammation and has been associated with hippocampal and cerebral damage [8]. Mast cells are a rich source of IL-6 and TNF [19]. In fact, mast cells are the only immune cells that store pre-formed TNF and can release it rapidly upon stimulation [20].

        Mast cells and cytokines such as IL-6 and TNF are also implicated in disruption of the blood–brain barrier (BBB) [2123], which may be malfunctioning or leaky in ASD as evidenced by the presence of circulating auto-antibodies directed against the fetal brain proteins [2427]. We had reported that the cytokine IL-33 synergizes with inflammatory neuropeptides to stimulate mast cells and result in increased vascular permeability [28]. IL-33 has been considered an alarmin, acting through mast cells to alert the innate immune system [29, 30], and has recently been linked to brain inflammation [3133].

        We have also reported that neurotensin (NT) and corticotropin-releasing hormone (CRH), secreted under stress, synergistically stimulate mast cells, leading to increase vascular permeability [34] and contribute to BBB disruption [35]. We further showed that NT stimulates mast cell secretion of vascular endothelial growth factor (VEGF) [36], which is also vasodilatory. NT also increases expression of CRH receptor-1 (CRHR-1) [37], activation of which by CRH increases allergic stimulation of human mast cells [38].

        NT is a vasoactive peptide originally isolated from the brain [39], but also found in the gut where it has been implicated in inflammation [40], and in increased intestinal permeability in rodents [41]. NT is also increased in the skin following acute stress, stimulates skin mast cells and increases vascular permeability in rodents [42]. NT stimulates rodent peritoneal mast cells to secrete histamine and elevates histamine plasma levels through activation of specific NT receptors (NTR) [4345]. Moreover, NT is rapidly degraded by mast cell proteases [34, 46] implying tight regulation of its activity.

        Mast cells are hemopoietic-derived tissue immune cells responsible for allergies, but also implicated in immunity [47] and inflammation [18]. Mast cells can produce both pro- and anti-inflammatory mediators [48] and may have immuno-modulatory functions [47, 4951]. It is, therefore, of interest that allergic-like reactions are common in ASD children [52, 53] implying activation of mast cells by non-allergic triggers [17]. The richest source of mast cells in the brain is the diencephalon [54] that regulates behavior, while the highest concentration of NTR is in the Broca area [55], which regulates language, known to be lost in many children with ASD. Mast cells are responsible for eliciting neutrophil infiltration that promotes inflammation [56]. Mast cell-microglial interactions are important in neuroinflammatory diseases [57, 58]. Microglia are the innate brain immune cells that are increasingly implicated in a number of neuropsychiatric diseases [59]. In fact, abnormal microglial growth and activation was recently reported in the brain of ASD patients [60, 61]. Microglia express NTR3, activation of which leads to their proliferation [62].

        NT has additional actions that are relevant to ASD (Table 1): it induces intestinal secretion and mobility [63], stimulates glial cell proliferation [64], and can facilitate seizures through activation of glutamate receptors [65]. In fact, the glutamate receptor mGluR5 was reported to be overactive in fragile X mice [66, 67], a condition associated with high risk of ASD. In other words, NT could contribute to ASD pathogenesis through different mechanisms (Figure 1).
        Table 1

        Neurotensin actions relevant to autism spectrum disorder (ASD) pathogenesis

        Effect

        Result

        Activation and proliferation of microglia

        Brain inflammation

        Activation of mast cells

        Blood–brain-barrier disruption and inflammation

        Disruption of gut-blood barrier

        Leaky gut and inflammation

        Mast cell stimulation, especially in the subgroup of ASD patients with allergic symptoms

        Augmentation of allergic symptoms

        Extracellular secretion of mitochondrial components that act as innate pathogens

        Inflammation

        Stimulation of glutamate receptors

        Neuronal damage

        Direct neurotoxicity

        Neuronal damage

        http://static-content.springer.com/image/art%3A10.1186%2F1742-2094-10-46/MediaObjects/12974_2013_815_Fig1_HTML.jpg
        Figure 1

        Diagrammatic representation of how stimulation of mast cells and microglia could lead to multiple effects that contribute brain inflammation and the pathogenesis and symptoms of autism. MCP, monocyte chemotactic protein.

        There is also support for increased oxidative stress [68] and some mitochondrial (mt) defects at least in subgroups of patients with ASD [69]. We showed that mtDNA is significantly increased in the serum of young autistic children [70], who also had significantly increased serum level of NT [71]; this triggers mast cells to secrete mtDNA [38] that acts as innate pathogen to stimulate mast cells [72] and other immune cells, leading to auto-inflammation [73]. Moreover, mtDNA can cause neuronal degeneration and altered behavior [74]. We believe that ASD originate from immune perinatal insults [75, 76] that activate ASD susceptibility genes leading to focal encephalitis (Table 2).
        Table 2

        Key pathologic processes in ASD *

        Change

        Pathologic processes

          ↑

        Allergic-like symptoms

          ↑

        Anti-brain protein auto-antibodies

          ↑

        Food intolerance

          ↑

        Brain and gut inflammatory markers

          ↑

        High anxiety and response to stress

          ↑

        Oxidative stress

          ↓

        Glutathione

          ↓

        Methylation, sulfation

        * Not present all ASD children.

        Epigenetic activation of ASD susceptibility genes

        In spite of the fact that almost 100 gene mutations have been identified in patients with ASD [77, 78], they do not explain more than a few percent of ASD cases [6]. High risk for developing ASD has been associated with mutations leading to decreased phosphatase and tensin homolog (PTEN) and tuberous sclerosis protein 1 and 2 (TSC1/2) [77]. These proteins are upstream inhibitors of the mammalian target of rapamycin (mTOR) [77, 79], which leads to microglia and mast cell proliferation [80, 81]. Activation of susceptibility genes is being increasingly invoked to explain ASD [7, 82]. A recent paper reported that offspring of maternal immune activation in mice led to increased IL-6 and IL-17, and contributed to ASD-related behaviors [9]; repopulation of control irradiated mice with bone marrow derived from affected mothers did not induce those effects suggesting the contribution of some epigenetic environmental influences. Stimulation of mTOR in subjects with overactive mTOR due to gene mutations, leading to low PTEN, would contribute to a form of epigenetic signal.

        Novel treatments

        Behavioral interventions are the most common treatment approaches [83], but do not address the core ASD symptoms [84, 85]. Psychotropic drugs are used much too often in ASD [8688]. Such drugs include antipsychotic medications [89], the newer atypical compounds [90, 91] risperidone [92, 93] and aripiprazole [94] for obsessive-compulsive symptoms, aggression and self-injury, as well as methylphenidate for hyperactivity [95]. However, two recent reviews concluded that there is insufficient evidence to support any benefit of psychotropic drugs [96] or selective serotonin re-uptake inhibitor (SSRIs) [97] in ASD. In fact, the SSRI citalopram may actually be detrimental [98], especially in children [99]. Moreover, a recent paper reported that citalopram administration perinataly altered cortical network function and led to ASD-like behaviors in rodents [100].

        Rapamycin and its analogs are mTOR inhibitors [101] and are being tried for treatment of ASD [102105] (Figure 2). Our preliminary results (not shown) indicate for the first time that the natural flavonoid luteolin [106] is more potent that rapamycin in its ability to inhibit human mast cell TNF release (Figure 2). A previous report also indicated that flavonoid-related epigallocatechin gallate (EGCG) is an mTOR inhibitor [107]. Luteolin may not only inhibit mTOR, but also has additional beneficial effects in brain inflammation. It inhibits oxidative stress [106], inflammation [106], mast cell degranulation [108], mast cell cytokine release [38], thimerosal-induced inflammatory mediator release [109], microglial activation and proliferation [110112], and auto-immune T cell activation [113, 114]. Luteolin is also protective against methylmercury-induced mitochondrial damage [115], is neuroprotective [116] and mimics brain-derived neurotrophic factor (BDNF) [117], which was recently associated with autistic-like-behavior in mice [118]. Finally, luteolin could reverse ASD-like behavior in mice [53], and was recently shown to have significant benefit in children with ASD [38, 119].
        http://static-content.springer.com/image/art%3A10.1186%2F1742-2094-10-46/MediaObjects/12974_2013_815_Fig2_HTML.jpg
        Figure 2

        Diagrammatic representation of the mTOR pathway, how it may lead to increased risk of autism and the inhibitory effect of luteolin. mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homolog; AKT, protein kinase B.

        Conclusions

        The prevalence of ASD continues to rise, but there is no clinically effective drug for the core ASD symptoms. Unfortunately, the lack of distinct pathogenesis and biomarkers makes it difficult to develop effective treatments. Stimulation of mTOR, which is already activated due to PTEN mutations, by NT, CRH and/or IL-33, could serve as novel targets for drug development. NTR and CRHR-1 antagonists could, therefore, be used in ASD, along with luteolin.

        Abbreviations

        ASD: 

        autism spectrum disorders

        BBB: 

        blood–brain barrier

        BDNF: 

        brain-derived neurotrophic factor

        CSF: 

        cerebrospinal fluid

        CRH: 

        corticotropin-releasing hormone

        EGCG: 

        epigallocatechin gallate

        IL: 

        interleukin

        MCP: 

        monocyte chemotactic protein

        mTOR: 

        mammalian target of rapamycin

        mt: 

        mitochondrial

        NT: 

        neurotensin

        NTR: 

        neurotensin receptor

        PTEN: 

        phosphatase and tensin homolog

        SSRI: 

        selective serotonin re-uptake inhibitor

        TNF: 

        tumor necrosis factor

        TSC1/2: 

        tuberous sclerosis protein 1 and 2

        VEGF: 

        vascular endothelial growth factor.

        Declarations

        Acknowledgements

        Aspects of the work discussed were funded in part by the Autism Research Institute, the National Autism Association, Safe Minds, and Theta Biomedical Consulting and Development Co. Inc. (Brookline, MA).

        Authors’ Affiliations

        (1)
        Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine
        (2)
        Department of Pharmacy, Tufts Medical Center
        (3)
        Department of Biochemistry, Tufts University School of Medicine
        (4)
        Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center
        (5)
        Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center
        (6)
        Graduate Program in Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University

        References

        1. Theoharides TC, Zhang B, Conti P: Decreased mitochondrial function and increased brain inflammation in bipolar disorder and other neuropsychiatric diseases. J Clin Psychopharmacol 2011, 31:685–687.PubMedView Article
        2. Hagberg H, Gressens P, Mallard C: Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol 2012, 71:444–457.PubMedView Article
        3. Fombonne E: Epidemiology of pervasive developmental disorders. Pediatr Res 2009, 65:591–598.PubMedView Article
        4. Johnson CP, Myers SM: Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007, 120:1183–1215.PubMedView Article
        5. McPartland J, Volkmar FR: Autism and related disorders. Handb Clin Neurol 2012, 106:407–418.PubMedView Article
        6. Abrahams BS, Geschwind DH: Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 2008, 9:341–355.PubMedView ArticlePubMed Central
        7. Williams SC: Genetics: searching for answers. Nature 2012, 491:S4-S6.PubMedView Article
        8. Hornig M, Weissenbock H, Horscroft N, Lipkin WI: An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci USA 1999, 96:12102–12107.PubMedView ArticlePubMed Central
        9. Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH: Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci USA 2012, 109:12776–12781.PubMedView ArticlePubMed Central
        10. Blenner S, Reddy A, Augustyn M: Diagnosis and management of autism in childhood. BMJ 2011, 343:d6238.PubMedView Article
        11. Rapin I, Tuchman RF: What is new in autism? Curr Opin Neurol 2008, 21:143–149.PubMedView Article
        12. Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M: How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 2008, 29:190–201.PubMedView Article
        13. Lanni KE, Schupp CW, Simon D, Corbett BA: Verbal ability, social stress, and anxiety in children with autistic disorder. Autism 2012, 16:123–138.PubMedView ArticlePubMed Central
        14. Herbert MR: Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 2010, 23:103–110.PubMedView Article
        15. Goines PE, Ashwood P: Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment. Neurotoxicol Teratol 2012.
        16. Onore C, Careaga M, Ashwood P: The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 2012, 26:383–392.PubMedView ArticlePubMed Central
        17. Theoharides TC, Angelidou A, Alysandratos KD, Zhang B, Asadi S, Francis K, Toniato E, Kalogeromitros D: Mast cell activation and autism. Biochim Biophys Acta 1822, 2012:34–41.
        18. Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, Kalogeromitros D: Mast cells and inflammation. Biochim Biophys Acta 1822, 2010:21–33.
        19. Norrby K: Mast cells and de novo angiogenesis: angiogenic capability of individual mast-cell mediators such as histamine, TNF, IL-8 and bFGF. Inflamm Res 1997,46(Suppl. 1):S7-S8.PubMed
        20. Zhang B, Weng Z, Sismanopoulos N, Asadi S, Therianou A, Alysandratos KD, Angelidou A, Shirihai O, Theoharides TC: Mitochondria distinguish granule-stored from de novo synthesized tumor necrosis factor secretion in human mast cells. Int Arch Allergy Immunol 2012,159(1):23–32.PubMedView ArticlePubMed Central
        21. Galli SJ: New concepts about the mast cell. N Engl J Med 1993, 328:257–265.PubMedView Article
        22. Theoharides TC, Doyle R: Autism, gut-blood–brain barrier and mast cells. J Clin Psychopharm 2008, 28:479–483.View Article
        23. Kim KS, Wass CA, Cross AS, Opal SM: Modulation of blood–brain barrier permeability by tumor necrosis factor and antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res 1992, 11:293–298.PubMed
        24. Rossi CC, Van de Water J, Rogers SJ, Amaral DG: Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders. Brain Behav Immun 2011, 25:1123–1135.PubMedView ArticlePubMed Central
        25. Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de Water J: Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology 2008, 29:226–231.PubMedPubMed Central
        26. Braunschweig D, Duncanson P, Boyce R, Hansen R, Ashwood P, Pessah IN, Hertz-Picciotto I, Van de Water J: Behavioral correlates of maternal antibody status among children with autism. J Autism Dev Disord 2012,42(7):1435–1445.PubMedView Article
        27. Braunschweig D, Van de Water J: Maternal autoantibodies in autism. Arch Neurol 2012, 69:693–699.PubMedView Article
        28. 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: IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci USA 2010, 107:4448–4453.PubMedView ArticlePubMed Central
        29. Moussion C, Ortega N, Girard JP: 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 2008, 3:e3331.PubMedView ArticlePubMed Central
        30. Enoksson M, Lyberg K, Moller-Westerberg C, Fallon PG, Nilsson G, Lunderius-Andersson C: Mast cells as sensors of cell injury through IL-33 recognition. J Immunol 2011, 186:2523–2528.PubMedView Article
        31. Zhao YY, Weir MA, Manno M, Cordy P, Gomes T, Hackam DG, Juurlink DN, Mamdani M, Moist L, Parikh CR, Paterson JM, Wald R, Yao Z, Garg AX: New fibrate use and acute renal outcomes in elderly adults: a population-based study. Ann Intern Med 2012, 156:560–569.PubMedView Article
        32. Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, Girard JP: Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain. J Immunol 2012, 188:3488–3495.PubMedView Article
        33. Chakraborty S, Kaushik DK, Gupta M, Basu A: Inflammasome signaling at the heart of central nervous system pathology. J Neurosci Res 2010, 88:1615–1631.PubMed
        34. Donelan J, Boucher W, Papadopoulou N, Lytinas M, Papaliodis D, Theoharides TC: Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc Natl Acad Sci USA 2006, 103:7759–7764.PubMedView ArticlePubMed Central
        35. Theoharides TC, Konstantinidou A: Corticotropin-releasing hormone and the blood–brain-barrier. Front Biosci 2007, 12:1615–1628.PubMedView Article
        36. Vasiadi M, Therianou A, Alysandratos KD, Katsarou-Katsari A, Petrakopoulou T, Theoharides A, Papadavid E, Stavrianeas N, Antoniou C, Kalogeromitros D, Theoharides TC: Serum neurotensin (NT) is increased in psoriasis and NT induces VEGF release from human mast cells. Br J Dermatol 2012, 166:1349–1352.PubMedView ArticlePubMed Central
        37. Alysandratos K-D, Asadi S, Angelidou A, Zhang B, Sismanopoulos N, Yang H, Critchfield A, Theoharides TC: Neurotensin and CRH interactions augment human mast cell activation. PLoS ONE 2012,7(11):e48934.PubMedView ArticlePubMed Central
        38. Asadi S, Theoharides TC: Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release, which is inhibited by luteolin. J Neuroinflam 2012, 9:85.View Article
        39. Carraway R, Leeman SE: The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 1973, 248:6854–6861.PubMed
        40. Tyler-McMahon BM, Boules M, Richelson E: Neurotensin: peptide for the next millennium. Regul Pept 2000, 93:125–136.PubMedView Article
        41. Carraway RE, Singer EA, Ferris CF, Mitra SP: Generation of immunoreactive neurotensin(s) and enkephalin(s) by pepsin-treatment of plasma. Adv Exp Med Biol 1986, 198 Pt B:169–179.PubMedView Article
        42. Singh LK, Pang X, Alexacos N, Letourneau R, Theoharides TC: Acute immobilization stress triggers skin mast cell degranulation via corticotropin-releasing hormone, neurotensin and substance P: a link to neurogenic skin disorders. Brain Behav Immunity 1999, 13:225–239.View Article
        43. Carraway R, Cochrane DE, Lansman JB, Leeman SE, Paterson BM, Welch HJ: Neurotensin stimulates exocytotic histamine secretion from rat mast cells and elevates plasma histamine levels. J Physiol 1982, 323:403–414.PubMedPubMed Central
        44. Feldberg RS, Cochrane DE, Carraway RE, Brown EB, Sawyer R, Hartunian M, Wentworth D: Evidence for a neurotensin receptor in rat serosal mast cells. Inflamm Res 1998, 47:245–250.PubMedView Article
        45. Barrocas AM, Cochrane DE, Carraway RE, Feldberg RS: Neurotensin stimulation of mast cell secretion is receptor-mediated, pertussis-toxin sensitive and requires activation of phospholipase C. Immunopharmacology 1999, 41:131–137.PubMedView Article
        46. Cochrane DE, Carraway RE, Boucher W, Feldberg RS: Rapid degradation of neutotensin by stimulated rat mast cells. Peptides 1991, 12:1187–1194.PubMedView Article
        47. Kalesnikoff J, Galli SJ: New developments in mast cell biology. Nat Immunol 2008, 9:1215–1223.PubMedView ArticlePubMed Central
        48. Kobayashi H, Ishizuka T, Okayama Y: Human mast cells and basophils as sources of cytokines. Clin Exp Allergy 2000, 30:1205–1212.PubMedView Article
        49. Galli SJ, Grimbaldeston M, Tsai M: Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 2008, 8:478–486.PubMedView ArticlePubMed Central
        50. Kawakami T: A crucial door to the mast cell mystery knocked in. J Immunol 2009, 183:6861–6862.PubMedView ArticlePubMed Central
        51. Piconese S, Costanza M, Musio S, Tripodo C, Poliani PL, Gri G, Burocchi A, Pittoni P, Gorzanelli A, Colombo MP, Pedotti R: Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient Kit W-sh/W-sh mice. Lab Invest 2011, 91:627–641.PubMedView Article
        52. Kogan MD, Blumberg SJ, Schieve LA, Boyle CA, Perrin JM, Ghandour RM, Singh GK, Strickland BB, Trevathan E, van Dyck PC: Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics 2009, 5:1395–1403.View Article
        53. Angelidou A, Alysandratos KD, Asadi S, Zhang B, Francis K, Vasiadi M, Kalogeromitros D, Theoharides TC: Brief report: “allergic symptoms” in children with autism spectrum disorders. More than meets the eye? J Autism Dev Disord 2011, 41:1579–1585.PubMedView Article
        54. Pang X, Letourneau R, Rozniecki JJ, Wang L, Theoharides TC: Definitive characterization of rat hypothalamic mast cells. Neuroscience 1996, 73:889–902.PubMedView Article
        55. Fassio A, Evans G, Grisshammer R, Bolam JP, Mimmack M, Emson PC: Distribution of the neurotensin receptor NTS1 in the rat CNS studied using an amino-terminal directed antibody. Neuropharmacology 2000, 39:1430–1442.PubMedView Article
        56. Walker ME, Hatfield JK, Brown MA: New insights into the role of mast cells in autoimmunity: evidence for a common mechanism of action? Biochim Biophys Acta 1822, 2012:57–65.
        57. Skaper SD, Giusti P, Facci L: Microglia and mast cells: two tracks on the road to neuroinflammation. FASEB J 2012, 26:3103–3117.PubMedView Article
        58. Skaper SD, Facci L: Mast cell-glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide. Philos Trans R Soc Lond B Biol Sci 2012, 367:3312–3325.PubMedView ArticlePubMed Central
        59. Nagai A, Nakagawa E, Hatori K, Choi HB, McLarnon JG, Lee MA, Kim SU: Generation and characterization of immortalized human microglial cell lines: expression of cytokines and chemokines. Neurobiol Dis 2001, 8:1057–1068.PubMedView Article
        60. Morgan JT, Chana G, Abramson I, Semendeferi K, Courchesne E, Everall IP: Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res 2012, 1456:72–81.PubMedView Article
        61. Rodriguez JI, Kern JK: Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol 2011, 7:205–213.PubMedView ArticlePubMed Central
        62. Martin S, Dicou E, Vincent JP, Mazella J: Neurotensin and the neurotensin receptor-3 in microglial cells. J Neurosci Res 2005, 81:322–326.PubMedView Article
        63. Riegler M, Castagliuolo I, Wang C, Wlk M, Sogukoglu T, Wenzl E, Matthews JB, Pothoulakis C: Neurotensin stimulates Cl(−) secretion in human colonic mucosa In vitro: role of adenosine. Gastroenterology 2000, 119:348–357.PubMedView Article
        64. Martin S, Vincent JP, Mazella J: Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J Neurosci 2003, 23:1198–1205.PubMed
        65. Ghanizadeh A: Targeting neurotensin as a potential novel approach for the treatment of autism. J Neuroinflammation 2010, 7:58.PubMedView ArticlePubMed Central
        66. Bear MF, Dolen G, Osterweil E, Nagarajan N: Fragile X: translation in action. Neuropsychopharmacology 2008, 33:84–87.PubMedView ArticlePubMed Central
        67. Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L: Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 2012, 74:49–56.PubMedView Article
        68. Rossignol DA, Frye RE: 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 2012,17(4):389–401.PubMedView ArticlePubMed Central
        69. Rossignol DA, Frye RE: Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol. Psychiatry 2012, 17:290–314.PubMedView ArticlePubMed Central
        70. Zhang B, Angelidou A, Alysandratos KD, Vasiadi M, Francis K, Asadi S, Theoharides A, Sideri K, Lykouras L, Kalogeromitros D, Theoharides TC: Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J Neuroinflammation 2010, 7:80.PubMedView ArticlePubMed Central
        71. Angelidou A, Francis K, Vasiadi M, Alysandratos K-D, Zhang B, Theoharides A, Lykouras L, Kalogeromitros D, Theoharides TC: Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflam 2010, 7:48.View Article
        72. 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: Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: relevance to atopic dermatitis. J Allergy Clin Immunol 2011, 127:1522–1531.PubMedView ArticlePubMed Central
        73. Zhang B, Asadi S, Weng Z, Sismanopoulos N, Theoharides TC: Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions. PLoS ONE 2012,7(12):e49767.PubMedView ArticlePubMed Central
        74. Lauritzen KH, Moldestad O, Eide L, Carlsen H, Nesse G, Storm JF, Mansuy IM, Bergersen LH, Klungland A: Mitochondrial DNA toxicity in forebrain neurons causes apoptosis, neurodegeneration, and impaired behavior. Mol Cell Biol 2010, 30:1357–1367.PubMedView ArticlePubMed Central
        75. Angelidou A, Asadi S, Alysandratos KD, Karagkouni A, Kourembanas S, Theoharides TC: Perinatal stress, brain inflammation and risk of autism-Review and proposal. BMC Pediatr 2012, 12:89.PubMedView ArticlePubMed Central
        76. Theoharides TC, Kempuraj D, Redwood L: Autism: an emerging ‘neuroimmune disorder’ in search of therapy. Exp Opin Pharmacother 2009, 10:2127–2143.View Article
        77. Aldinger KA, Plummer JT, Qiu S, Levitt P: SnapShot: genetics of autism. Neuron 2011, 72:418.PubMedView Article
        78. Betancur C: Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 2011, 1380:42–77.PubMedView Article
        79. Zhou J, Parada LF: PTEN signaling in autism spectrum disorders. Curr Opin Neurobiol 2012,22(5):873–879.PubMedView Article
        80. Smrz D, Kim MS, Zhang S, Mock BA, Smrzova S, DuBois W, Simakova O, Maric I, Wilson TM, Metcalfe DD, Gilfillan AM: mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells. Blood 2011, 118:6803–6813.PubMedView ArticlePubMed Central
        81. Shang YC, Chong ZZ, Wang S, Maiese K: Erythropoietin and Wnt1 govern pathways of mTOR, Apaf-1, and XIAP in inflammatory microglia. Curr Neurovasc Res 2011, 8:270–285.PubMedView ArticlePubMed Central
        82. Weiss LA, Arking DE, Daly MJ, Chakravarti A: A genome-wide linkage and association scan reveals novel loci for autism. Nature 2009, 461:802–808.PubMedView ArticlePubMed Central
        83. Gerhard T, Chavez B, Olfson M, Crystal S: National patterns in the outpatient pharmacological management of children and adolescents with autism spectrum disorder. J Clin Psychopharmacol 2009, 29:307–310.PubMedView Article
        84. Lang R, Mahoney R, El Zein F, Delaune E, Amidon M: Evidence to practice: treatment of anxiety in individuals with autism spectrum disorders. Neuropsychiatr Dis Treat 2011, 7:27–30.PubMedView ArticlePubMed Central
        85. Warren Z, McPheeters ML, Sathe N, Foss-Feig JH, Glasser A, Veenstra-Vanderweele J: A systematic review of early intensive intervention for autism spectrum disorders. Pediatrics 2011, 127:e1303-e1311.PubMedView Article
        86. Munshi KR, Gonzalez-Heydrich J, Augenstein T, D’Angelo EJ: Evidence-based treatment approach to autism spectrum disorders. Pediatr Ann 2011, 40:569–574.PubMedView Article
        87. Nazeer A: Psychopharmacology of autistic spectrum disorders in children and adolescents. Pediatr Clin North Am 2011, 58:85–97.PubMedView Article
        88. Parikh MS, Kolevzon A, Hollander E: Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability. J Child Adolesc Psychopharmacol 2008, 18:157–178.PubMedView Article
        89. Posey DJ, Stigler KA, Erickson CA, McDougle CJ: Antipsychotics in the treatment of autism. J Clin Invest 2008, 118:6–14.PubMedView ArticlePubMed Central
        90. Chavez B, Chavez-Brown M, Sopko MA Jr, Rey JA: Atypical antipsychotics in children with pervasive developmental disorders. Paediatr Drugs 2007, 9:249–266.PubMedView Article
        91. McDougle CJ, Stigler KA, Erickson CA, Posey DJ: Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry 2008,69(Suppl 4):15–20.PubMed
        92. McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, Arnold LE, Lindsay R, Nash P, Hollway J, McDougle CJ, Posey D, Swiezy N, Kohn A, Scahill L, Martin A, Koenig K, Volkmar F, Carroll D, Lancor A, Tierney E, Ghuman J, Gonzalez NM, Grados M, Vitiello B, Ritz L, Davies M, Robinson J, McMahon D: Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002, 347:314–321.PubMedView Article
        93. Scott LJ, Dhillon S: Risperidone: a review of its use in the treatment of irritability associated with autistic disorder in children and adolescents. Paediatr Drugs 2007, 9:343–354.PubMedView Article
        94. Curran MP: Aripiprazole: in the treatment of irritability associated with autistic disorder in pediatric patients. Paediatr Drugs 2011, 13:197–204.PubMedView Article
        95. Research Units on Pediatric Psychparmacology Autism Network: Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005, 62:1266–1274.View Article
        96. McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-Vanderweele J: A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics 2011, 127:e1312-e1321.PubMedView Article
        97. Williams K, Wheeler DM, Silove N, Hazell P: Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev 2010, 8:CD004677.PubMed
        98. 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: 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 2009, 66:583–590.PubMedView ArticlePubMed Central
        99. Volkmar FR: Citalopram treatment in children with autism spectrum disorders and high levels of repetitive behavior. Arch Gen Psychiatry 2009, 66:581–582.PubMedView Article
        100. Correll CU, Kratochvil CJ, March JS: Developments in pediatric psychopharmacology: focus on stimulants, antidepressants, and antipsychotics. J Clin Psychiatry 2011, 72:655–670.PubMedView Article
        101. Zhou H, Luo Y, Huang S: Updates of mTOR inhibitors. Anticancer Agents Med Chem 2010, 10:571–581.PubMedView ArticlePubMed Central
        102. Ehninger D, Silva AJ: Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders. Trends Mol Med 2011, 17:78–87.PubMedView ArticlePubMed Central
        103. Sahin M: Targeted treatment trials for tuberous sclerosis and autism: no longer a dream. Curr Opin Neurobiol 2012,22(5):895–901.PubMedView ArticlePubMed Central
        104. de Vries PJ: Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex. Neurotherapeutics. 2010, 7:275–282.PubMedView Article
        105. Hampson DR, Gholizadeh S, Pacey LK: Pathways to drug development for autism spectrum disorders. Clin Pharmacol Ther 2012, 91:189–200.PubMedView Article
        106. Middleton E Jr, Kandaswami C, Theoharides TC: The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev 2000, 52:673–751.PubMed
        107. Van Aller GS, Carson JD, Tang W, Peng H, Zhao L, Copeland RA, Tummino PJ, Luo L: Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. Biochem Biophys Res Commun 2011, 406:194–199.PubMedView Article
        108. Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H: Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy 2000, 30:501–508.PubMedView Article
        109. Asadi S, Zhang B, Weng Z, Angelidou A, Kempuraj D, Alysandratos KD, Theoharides TC: Luteolin and thiosalicylate inhibit HgCl(2) and thimerosal-induced VEGF release from human mast cells. Int J Immunopathol Pharmacol 2010, 23:1015–1020.PubMed
        110. Dirscherl K, Karlstetter M, Ebert S, Kraus D, Hlawatsch J, Walczak Y, Moehle C, Fuchshofer R, Langmann T: Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation 2010, 7:3.PubMedView ArticlePubMed Central
        111. Jang S, Dilger RN, Johnson RW: Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J Nutr 2010, 140:1892–1898.PubMedView ArticlePubMed Central
        112. Kao TK, Ou YC, Lin SY, Pan HC, Song PJ, Raung SL, Lai CY, Liao SL, Lu HC, Chen CJ: Luteolin inhibits cytokine expression in endotoxin/cytokine-stimulated microglia. J Nutr Biochem 2011, 22:612–624.PubMedView Article
        113. Kempuraj D, Tagen M, Iliopoulou BP, Clemons A, Vasiadi M, Boucher W, House M, Wolferg A, Theoharides TC: Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell dependent stimulation of Jurkat T cells. Br J Pharmacol 2008, 155:1076–1084.PubMedView ArticlePubMed Central
        114. Verbeek R, Plomp AC, van Tol EA, van Noort JM: The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells. Biochem Pharmacol 2004, 68:621–629.PubMedView Article
        115. Franco JL, Posser T, Missau F, Pizzolatti MG, Dos Santos AR, Souza DO, Aschner M, Rocha JB, Dafre AL, Farina M: Structure-activity relationship of flavonoids derived from medicinal plants in preventing methylmercury-induced mitochondrial dysfunction. Environ Toxicol Pharmacol 2010, 30:272–278.PubMedView ArticlePubMed Central
        116. Chen HQ, Jin ZY, Wang XJ, Xu XM, Deng L, Zhao JW: Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation. Neurosci Lett 2008, 448:175–179.PubMedView Article
        117. Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K: A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci USA 2010, 107:2687–2692.PubMedView ArticlePubMed Central
        118. Sadakata T, Shinoda Y, Oka M, Sekine Y, Sato Y, Saruta C, Miwa H, Tanaka M, Itohara S, Furuichi T: Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice. Proc Natl Acad Sci USA 2012,109(51):21104–21109.PubMedView ArticlePubMed Central
        119. Theoharides TC, Asadi S, Panagiotidou S: A case series of a luteolin formulation (Neuroprotek®) in children with autism spectrum disorders. Intl J Immunopathol Pharmacol 2012, 25:317–323.

        Copyright

        © Theoharides et al.; licensee BioMed Central Ltd. 2013

        This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

        Advertisement