CNS Cytokines 375 References Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S et al (2000) Inflammation and Alzheimer’s disease. Neurobiol of Aging 21:383–421 Andjelkovic AV, Pachter J (1998) Central nervous system endothelium in neuroinflammatory, neuroinfectious, and neurodegenerative disease. J Neurosci Res 51:423–430 Andras I, Rha GB, Huang W, Eum SY, Couraud P-O, Romero IA, Hennig B, Toborek M (2008) Simvastatin protects against amyloid β and HIV-1 Tat-induced promoter activities of inflammatory genes in brain endothelial cells. Mol Pharmacol 73:1424–1433 Angstwurm K, Hanisch U-K, Gassemi T, Bille MB, Prinz M, Dirnagl U, Kettenmann H, Weber JR (2004) Tyrosine kinase inhibition reduces inflammation in the acute stage of experimental pneumococcal meningitis. Infect Immun 72:3294–3298 Anisman H (2004) Considering cytokine panels. Brain Behav Immun 18:221–222 Anthony D, Dempster R, Fearn S, Clements J, Wells G, Perry H, Walker K (1998) CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown. Curr Biol 8:923–926 Antony JM, Ellestad KK, Hammond R, Imaizumi K, Mallot F, Warren KG, Power C (2007) The human endogenous retrovirus envelope glycoprotein, syncytin-1, regulates neuroinflammation and its receptor expression in multiple sclerosis: A role for endoplasmic reticulum chaperones in astrocytes. J Immunol 179:1210–1224 Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S, Badger AM, White RF, McVey MJ, Legos JJ, Erhardt JA, Nelson AH, Ohlstein EH, Hunter AJ, Ward K, Smith BR, Adams JL, Parsons AA (2001) SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. J Pharmacol Exp Ther 296:312–321 Becaria A, Lahiri DK, Bondy SC, Chen D, Hamadeh A, Li H, Taylor R, Campbell A (2006) Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain. J Neuroimmunol 176:16–23 Becher B, Bechmann I, Greter M (2006) Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J Mol Med 84:532–543 Becher B, Prat A, Antel JP (2000) Brain-immune connection: Immune-regulatory properties of CNS-resident cells. GLIA 29:293–304 Biber K, Zuurman MW, Dijkstra IM, Boddeke HWGM (2002) Chemokines in the brain: neuroimmunology and beyond. Curr Opin Pharmacol 2:63–68 Block ML, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanism. Nat Rev Neurosci 8:57–69 Boche D, Cunningham C, Docagne F, Scott H, Perry VH (2006) TGFβ1 regulates the inflammatory response during chronic neurodegeneration. Neurobiol Dis 22:638–650 Bodles AM, Barger SW (2004) Cytokines and the aging brain – what we don’t know might help us. Trends Neurosci 27:621–626 Bossu P, Ciaramella A, Salani F, Bizzoni F, Varsi E, De Iulio F, Giubilei F, Gianni W, Trequattrini A, Moro ML, Bernardini S, Caltagirone C, Spalletta G (2008) Interleukin-18 produced by peripheral blood cells is increased in Alzheimers disease and correlates with cognitive impairment. Brain Behav Immun 22:487–492 Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27:325–355 Bugno M, Witek B, Bereta J, Bereta M, Edwards DR, Kordula T (1999) Reprogramming of TIMP- 1 and TIMP-3 expression profiles in brain microvascular endothelial cells and astrocytes in response to proinflammatory cytokines. FEBS Lett 448:9–14 Cagnin A, Gerhard A, Banati RB (2002) In vivo imaging of neuroinflammation. Eur Neuropsycopharm 12:581–586 376 J. Kasten-Jolly and D.A. Lawrence Calvo C-F, Amigou E, Desaymard C, Glowinski J (2005) A pro- and an anti-inflammatory cytokine are synthesized in distinct brain macrophage cells during innate activation. J Neuroimmunol 170:21–30 Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone MB, Mucke L (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin-6. Proc Natl Acad Sci USA 90:10061–10065 Campbell SJ, Deacon RMJ, Jiang Y, Ferrari C, Pitossi FJ, Anthony DC (2007) Overexpression of IL-1β by adenoviral-mediated gene transfer in the rat brain cause a prolonged hepatic chemokine response, axonal injury and the suppression of spontaneous behaviour. Neurobiol Dis 27:151–163 Cartmell T, Luheshi GN, Rothwell NJ (1999) Brain sites of action of endogenous interleukin-1 in the febrile response to localized inflammation in the rat. J Physiol 518:585–594 Choi HB, Ryu JK, Kim SU, McLarnon JG (2007) Modulation of the puinergic P2X 7 receptor attenuates lipopolysaccharide-mediated microglial activation and neuronal damage in inflamed brain. J Neurosci 27:4957–4968 Chong ZZ, Lin S-H, Kang J-Q, Maiese K (2003) The tyrosine phosphatase SHP2 modulates MAP kinase-38 and caspase 1 and 3 to foster neuronal survival. Cell Mol Neurobiol 23: 561–578 Ciccarelli R, Ballerini P, Sabatino G, Rathbone MP, D’Onofrio M, Caciagli F, DiIorio P (2001) Involvement of astrocytes in purine-mediated reparative processes in the brain. Dev Neurosci 19:395–414 Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE (2000) Inflammatory mecha- nisms in Alzheimer’s disease: inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists. J Neurosci 20:558–567 Cordova FM, Rodrigues ALS, Giacomelli MBO, Olivera CS, Posser T, Dunkley PR, Leal RB (2003) Lead stimulates ERK 1/2 and p38 MAPK phosphorylation in the hippocampus of immature rats. Brain Res 998:65–72 Cotman CW, Berchtold NC, Christie L-A (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30:464–472 Cotran RS, Kumar V, Robbins SL (eds) (1994) Pathologic basis of disease. W.B. Saunders, Philadelphia, PA, pp 39–86 Croll SD, Ransohoff RM, Cai N, Zhang Q, Martin FJ, Wei T, Kasselman LJ, Kintner J, Murphy AJ, Yancopoulos GD, Wiegand SJ (2004) VEGF-mediated inflammation precedes angiogenesis in adult brain. Exp Neurol 187:388–402 Cruikshank WW, Kornfeld H, Center DM (2000) Interleukin-16. J Leukocyte Biol 67:757–766 Cunningham C, Konsman J-P, Cartmell T (2002) Cytokines and the ageing brain. Trends Neurosci 25:546–547 Curran B, O’Connor JJ (2001) The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro. Neuroscience 108:83–90 Dantzer R, Bluthe R-M, Castanon N, Kelley KW, Konsman J-P, Laye S, Lestage J, Parnet P (2007) Cytokines, sickness behavior, and depression. In: Ader R (ed) Psychoneuroimmunology, 4th edn, vol 1. Elsevier, Inc., London, pp 281–318 Dantzer R, O’Conner JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–57 Dinarello CA (2006) Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83(Suppl):447S–455S Dyatlov VA, Lawrence DA (2002) Neonatal lead exposure potentiates sickness behavior induced by Listeria monocytogenes infection of mice. Brain Behav Immun 16(4):477–492 Dyatlov V, Platoshin AV, Lawrence DA, Carpenter DO (1998) Lead potentiates cytokine- and glutamate-mediated increases in permeability of the blood-brain barrier. Neurotoxicology 19:283–292 CNS Cytokines 377 Eikelenboom E, Veerhuis R (1996) The role of complement and activated microglia in the pathogenesis of Alzheimer’s disease. Neurobiol Aging 17:673–680 Eikelenboom P, Veerhuls R, Scheper W, Rozemuller AJM, van Gool WA, Hoozemans JJM (2006) The significance of neuroinflammation in understanding Alzheimer’s disease. J Neural Trans 113:1685–1695 Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–144 Farooqui AA, Horrocks LA, Farooqui T (2007) Modulation of inflammation in brain: a matter of fat. J Neurochem 101:577–599 Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Buhrer C, Stahel PF (2005) IL-18: a key player in neuroinflammation and neurodegeneration. Trends Neurosci 28:487–493 Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, Panther E, di Virgilio F (2006) The P2X 7 receptor: a key player in IL-1 processing and release. J Immunol 176: 3877–3883 Fitch MT, Silver J (1997) Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurobiol 148: 587–603 Floyd RA (1999) Neuroinflammatory processes are important in neurodegenerative diseases: an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Radic Biol Med 26: 1346–1355 Galazka G, Stasiolek M, Walczak A, Jurewicz A, Zylicz A, Brosnan CF, Raine CS, Selmaj KW (2006) Brain-derived heat shock protein 70-peptide complexes induce NK cell-dependent tolerance to experimental autoimmune encephalomyelitis. J Immunol 176:1588–1599 Galea E, Heneka MT, Russo CD, Feinstein DL (2003) Intrinsic regulations of brain inflammatory responses. Cell Mol Neurobiol 23:625–635 Grammas P, Ovase R (2002) Cerebrovascular transforming growth factor-β contributes to inflam- mation in the Alzheimer’s disease brain. Am J Pathol 160:1583–1587 Hamby ME, Hewett JA, Hewett SJ (2006) TGF-β1 potentiates astrocytic nitric oxide production by expanding the population of astrocytes that express NOS-2. GLIA 54:566–577 Hauss-Wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL (1998) Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease. Brain Res 780: 294–303 Heese K, Hock C, Otten U (1998) Inflammatory signals induce neurotrophin expression in human microglial cells. J Neurochem 70:699–707 Horai BR, Asano M, Sudo K, Kanuka H, Suzuki M, Nishihara M, Takahashi M, Iwakura Y (1998) Production of mice deficient in genes for interleukin (IL)-1α,IL-1β,IL-1α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion. J Exp Med 187:1463–1475 Hsieh M-F, Lai S-L, Chen J-P, Sung J-M, Lin Y-L, Wu-Hsieh BA, Gerard C, Luster A, Liao F (2006) Both CXCR3 and CXCL10/IFN-inducible protein 10 are required for resistance to primary infection by Dengue virus. J Immunol 177:1855–1863 Hudson CA, Christophi GP, Gruber RC, Wilmore JR, Lawrence DA, Massa PT (2008) Induction of IL-33 expression and activity in central nervous system glia. J Leukoc Biol 84: 631–643 Hull M, Fiebich BL, Lieb K, Strauss S, Berger M, Volk B, Bauer J (1996) Interleukin-6-associated inflammatory processes in Alzheimer’s disease: new therapeutic options. Neurobiol Aging 17:795–800 Ichiyama T, Zhao H, Catania A, Furukawa S, Lipton JM (1999) α-melanocyte-stimulating hormone inhibits NF-κB activation and IκBα degradation in human glioma cells and in experimental brain inflammation. Exp Neurol 157:359–365 Inoue W, Poole S, Bristow AF, Luheshi GN (2006) Leptin induces cyclooxygenase-2 via an interaction with interleukin-1β in the rat brain. Eur J Neurosci 24:2233–2245 378 J. Kasten-Jolly and D.A. Lawrence Ivanov S, Dragoi A-M, Wang X, Dallacosta C, Louten J, Musco G, Sitia G, Yap GS, Wan Y, Biron CA, Bianchi ME, Wang H, Chu W-M (2007) A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood 110:1970–1981 Iwai T, Ito S, Tanimitsu K, Udagawa S, Oka J-I (2006) Glucagon-like peptide-1 inhibits LPS- induced IL-1β production in cultured rat astrocytes. Neurosci Res 55:352–360 Jafarian-Tehrani M, Sternberg EM (1999) Animal models of neuroimmune interactions in inflam- matory diseases. J Neuroimmunol 100:13–20 Jones NC, Prior MJW, Burden-The E, Marsden CA, Morris P, Murphy S (2005) Antagonism of the interleukin-1 receptor following traumatic brain injury in the mouse reduces the number of nitric oxide synthase-2-positive cells and improves anatomical and functional outcomes. Eur J Neurosci 22:72–78 Joseph JA, Shukitt-Hale B, Casadesus G, Fisher D (2005) Oxidative stress and inflammation in brain aging: nutritional considerations. Neurochem Res 30:927–935 Jou I, Lee JH, Park SY, Yoon HJ, Joe E-H, Park EJ (2006) Gangliosides trigger inflammatory responses via TLR4 in brain glia. Am J Pathol 168:1619–1630 Juttler E, Bonmann E, Spranger M, Kolb-Bachofen V, Suschek CV (2007) A novel role of interleukin-1-converting enzyme in cytokine-mediated inducible nitric oxide synthase gene expression: Implications for neuroinflammatory diseases. Mol Cell Neurosci 34:612–620 Kalaria RN, Cohen DL, Premkumar DRD (1996) Cellular aspects of the inflammatory response in Alzheimer’s disease. Neurodegeneration 5:497–503 Kanemaru K, Meckelein B, Marshall CL, Sipe JD, Abraham CR (1996) Synthesis and secre- tion of active α 1 -antichymotrypsin by murine primary astrocytes. Neurobiol Aging 17: 767–771 Karman J, Chu HH, Co DO, Seroogy CM, Sandor M, Fabry Z (2006) Dendritic cells amplify T cell-mediated immune responses in the central nervous system. J Immunol 177:7750–7760 Kielian T, Hickey WF (2000) Proinflammatory cytokine, chemokine, and cellular adhesion molecule expression during the acute phase of experimental brain abscess development. Am J Pathol 157:647–658 Kifle Y, Monnier J, Chesrown SE, Raizada MK, Nick HS (1996) Regulation of the manganese superoxide dismutase and inducible nitric oxide synthase gene in rat neuronal and glial cells. J Neurochem 66:2128–2135 Kim J-B, Choi JS, Yu Y-M, Nam K, Piao C-S, Kim S-W, Lee M-H, Han P-L, Park J-S, Lee J-K (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26:6413–6421 Kim J-B, Lim C-M, Yu Y-M, Lee J-K (2008) Induction and subcellular localization of high- mobility group box-1 (HMGB1) in the postischemic rat brain. J Neurosci Res 86:1125–1131 Kim W-G, Mohney RP, Wilson B, Jeohn G-H, Liu B, Hong J-S (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci 20:6309–6316 Kim OS, Park EJ, Joe E-H, Jou I (2002) JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells. J Biol Chem 277:40594–40601 Kong G-Y, Peng Z-C, Costanzo C, Kristensson K, Bentivoglio M (2000) Inducible nitric oxide synthase expression elicited in the mouse brain by inflammatory mediators circulating in the cerebrospinal fluid. Brain Res 878:105–118 Konsman JP, Vigues S, Mackerlova LM, Bristow A, Blomqvist A (2004) Rat brain vascu- lar distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. J Comp Neurol 472: 113–129 Krasowska-Zoladek A, Banaszewska M, Kraszpulski M, Konat GW (2007) Kinetics of inflam- matory response of astrocytes induced by TLR3 and TLR4 ligation. J Neurosci Res 85: 203–212 Kurschner C, Yuzaki M (1999) Neuronal interleukin-16 (NIL-16): a dual function PDZ domain protein. J Neurosci 19:7770–7780 CNS Cytokines 379 Lacroix S, Rivest S (1998) Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain. J Neurochem 70:452–466 Laflamme N, Rivest S (1999) Effects of systemic immunogenic insults and circulating proin- flammatory cytokines on the transcription of the inhibitory factor κBα within specific cellular populations of the rat brain. J Neurochem 73:309–321 Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27: 2596–2605 Lassmann H (2007) Multiple sclerosis: is there neurodegeneration independent from inflamma- tion? J Neurological Sci 259:3–6 Lawrence DA (1981) In vivo and in vitro effects of lead on humoral and cell-mediated immunity. Infect Immun 31:36–143 Leal RB, Ribeiro SJ, Posser T, Cordova FM, Rigon AP, Filho EZ, Bainy ACD (2006) Modulation of ERK1/2 and p38 MAPK by lead in the cerebellum of Brazilian catfish Rhamdia quelen. Aquat Toxicol 77:98–104 Lee H, Cha S, Lee M-S, Cho G-J, Choi WS, Suk K (2003) Role of antiproliferative B cell transla- cation gene-1 as an apoptotic sensitizer in activation-induced cell death of brain microglia. J Immunol 171:5802–5811 Lee SJ, Drabik K, Van Wagoner NJ, Lee S, Choi C, Dong Y, Benveniste B (2000a) ICAM-1- induced expression of proinflammatory cytokines in astrocytes: involvement of extracellu- lar signal-regulated kinase and p38 mitogen-activated protein kinase pathways. J Immunol 165:4658–4666 Lee J-M, Grabb MC, Zipfel GJ, Choi DW (2000b) Brain tissue responses to ischemia. J Clin Invest 106:723–731 Lee JH, Park EJ, Kim OS, Kim HY, Joe E-H, Jou I (2005) Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells. GLIA 50:66–76 Li S, Ballou LR, Morham SG, Blatteis CM (2001) Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1β. Brain Res 910:163–173 Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA (2003) Phosphatidylserine receptor is required for clearance of apoptotic cells. Science 302:1560–1563 Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C, Casadei V, Grimaldi LME (2000) Increased plasma levels of interleukin-1, interleukin-6 and α-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain. J Neuroimmunol 103:97–102 Lindahl LS, Bird L, Legare ME, Mikeska G, Bratton GR, Tiffany-Castiglioni E (1999) Differential ability of astroglia and neuronal cells to accumulate lead: dependence on cell type and on degree of differentiation. Toxicol Sci 50:236–243 Lukiw WJ, Percy ME, Kruck TP (2005) Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture. J Inorg Biochem 99: 1895–1898 Luo J, Ho PP, Buckwalter MS, Hsu T, Lee LY, Zhang H, Kim D-K, Kim S-J, Gambhir SS, Steinman L, Wyss-Coray T (2007) Glia-dependent TGF-β signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis. J Clin Invest 117:3306–3315 Makwana M, Jones LL, Cuthill D, Heuer H, Bohatschek M, Hristova M, Friedrichsen S, Ormsby I, Bueringer D, Koppius A, Bauer K, Doetschman T, Raivich G (2007) Endogenous transforming growth factor β1 suppresses inflammation and promotes survival in adult CNS. J Neurosci 27:11201–11213 Martino G, Furlan R, Brambilla E, Bergami A, Ruffini F, Gironi M, Poliani PL, Grimaldi LME, Comi G (2000) Cytokines and immunity in multiple sclerosis: the dual signal hypothesis. J Neuroimmunol 109:3–9 380 J. Kasten-Jolly and D.A. Lawrence Martinon F, Gaide O, Pétrilli V, Mayor A, Tschopp J (2007) NALP inflammasomes: a central role in innate immunity. Semin Immunopathol 29:213–229 Mastronardi C, Whelan F, Yildiz OA, Hannestad J, Elashoff D, McCann SM, Licinia J, Wong M-L (2007) Caspase-1 deficiency reduces inflammation-induced brain transcription. Proc Natl Acad Sci 104:7205–7210 Matyszak MK (1998) Inflammation in the CNS: balance between immunological privilege and immune responses. Prog Neurobiol 56:19–35 Mennicken F, Maki R, de Souza EB, Quirion R (1999) Chemokinases and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. TiPS 20:73–78 Mesples B, Fontaine RH, Lelievre V, Launay J-M, Gressens P (2005) Neuronal TGF-β 1 medi- ates IL-9/mast cell interaction and exacerbates excitotoxicity in newborn mice. Neurobiol Dis 18:193–205 Mielke K, Herdegen T (2000) JNK and p38 stresskinases – degenerative effectors of signal- transduction-cascades in the nervous system. Prog Neurobiol 61:45–60 Milner R, Campbell IL (2006) Increased expression of the β4andα5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system. Mol Cell Neurosci 33:429–440 Muceniece R, Zvejniece L, Kirjanova O, Liepinsh E, Krigere L, Baumane L, Kalvinish I, Wikberg JES, Dambrova M (2004) β-andγ-melanocortins inhibit lipopolysaccharide induced nitric oxide production in mice brain. Brain Res 995:7–13 Nhan TQ, Liles C, Schwartz SM (2006) Physiological functions of caspases beyond cell death. Am J Pathol 169:729–737 Niederkorn JY (2006) See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol 7:354–359 Norris CM, Kadish I, Blalock EM, Chen K-C, Thibault V, Porter NM, Landfield PW, Kraner SD (2005) Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer’s models. J Neurosci 25:4649–4658 O’Callaghan JP, Sriram K (2005) Glial fibrillary acidic protein and related glial proteins as biomarkers of neurotoxicity. Expert Opin Drug Saf 4:433–442 Odemis V, Moepps B, Gierschik P, Engele J (2002) Interleukin-6 and cAMP induce stromal cell-derived factor-1 chemotaxis in astroglia by up-regulating CXCR4 cell surface expression. J Biol Chem 277:39801–39808 Pahan K, Khan M, Singh I (2000) Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced ceramide production through the activation of phosphatidylinositol 3-kinase. J Neurochem 75:576–582 Pannu R, Singh AK, Singh I (2005) A novel role of lactosylceramide in the regulation of tumor necrosis factorα-mediated proliferation of rat primary astrocytes. J Biol Chem 280: 13742–13751 Pasinetti GM (1998) Cyclooxygenase and inflammation in Alzheimer’s disease: experimental approaches and clinical interventions. J Neurosci Res 54:1–6 Patel HC, Boutin H, Allan SM (2003) Interleukin-1 in the brain: mechanism of action in acute neurodegeneration. Ann N Y Acad Sci 992:39–47 Patkai J, Mesples B, Dommergues M-A, Fromont G, Thornton EN, Renauld J-C, Evrard P, Gressens P (2001) Deleterious effects of IL-9-activated mast cells and neuroprotection by antihistamine drugs in the developing mouse brain. Pediatr Res 50:222–230 Pinteaux E, Inoue W, Schmidt L, Molina-Holgado F, Rothwell NJ, Luheshi GN (2007) Leptin induces interleukin-1β release from rat microglial cells through a caspase 1 independent mechanism. J Neurochem 102:826–833 Pollmacher T, Haack M, Schuld A, Reichenberg A, Yirmiya R (2002) Low levels of circulat- ing inflammatory cytokines – Do they affect human brain functions? Brain Behav Immun 16: 525–532 Quan N, Banks WA (2007) Brain-immune communication pathways. Brain Behav Immun 21: 727–735 CNS Cytokines 381 Quan N, Mhlanga JDM, Whiteside MB, McCoy AN, Kristensson K, Herkenham M (1999) Chronic overexpression of proinfammatory cytokines a nd histopathology in the brains of rats infected with Trypanosoma brucei. J Comp Neurobiol 414:114–130 Rao N, Nguyen S, Ngo K, Fung-Leung W-P (2005) A novel splice variant of interlekin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory signaling. Mol Cell Biol 25:6521–6532 Rather LJ (1971) Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added by Galen to the four cardinal signs of Celsus. Bull N Y Acad Med 47:303–322 Razmiafshari M, Zawia NH (2000) Utilization of a synthetic peptide as a tool to study the interac- tion of heavy metals with the zinc finger domain of proteins critical for gene expression in the developing brain. Toxicol Appl Pharmacol 166:1–12 Rivest S (2003) Molecular insights on the cerebral innate immune system. Brain Behav Immun 17:13–19 Rosales-Corral S, Tan D-X, Reiter RJ, Valdivia-Velazquez M, Acosta-Martinez JP, Ortiz GG (2004) Kinetics of the neuroinflammation-oxidative stress correlation in rat brain follow- ing the injection of fibrillar amyloid-β onto the hippocampus in vivo. J Neuroimmunol 150:20–28 Rummel C, Hubschle T, Gerstberger R, Roth J (2004) Nuclear translocation of the transcription factor STAT3 in the guinea pig brain during systemic or localized inflammation. J Physiol 557:671–687 Sapirstein A, Saito H, Texel SJ, Samad TA, O’Leary E, Bonventre JV (2005) Cytosolic phospho- lipase A 2 α regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation. Am J Physiol Regul Integr Comp Physiol 288:R1774–R1782 Sheng JG, Ito K, Skinner RD, Mrak RE, Rovnaghi CR, van Eldik LJ, Griffen WST (1996) In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurbiol Aging 17:761–766 Shepherd CE, Goyette J, Utter V, Rahimi F, Yang Z, Geczy CL, Halliday GM (2006) Inflammatory S100A9 and S100A12 proteins in Alzheimer’s disease. Neurobiol Aging 27:1554–1563 Singh I, Pahan K, Khan M, Singh AK (1998) Cytokine-mediated induction of ceramide production is redox-sensitive. J Biol Chem 273:20354–20362 Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702 Stasiolek M, Gavrilyuk V, Sharp A, Horvath P, Selmaj K, Feinstein DL (2000) Inhibitory and stimulatory effects of lactacystin on expression of nitric oxide synthase type 2 in brain glial cells. J Biol Chem 275:24847–24856 Steffensen SC, Campbell IL, Henriksen SJ (1994) Site-specific hippocampal pathophysiology due to cerebral overexpression of interleukin-6 in transgenic mice. Brain Res 652:149–153 Stehlit C, Dorfleutner A (2007) COPs and POPs: modulators of inflammasome activity. J Immunol 179:7993–7998 Stolp HB, Dziegielewska KM, Ek CJ, Habgood MD, Lane MA, Potter AM, Saunders NR (2005) Breakdown of the blood-brain barrier to proteins in white matter of the developing brain following systemic inflammation. Cell Tissue Res 320:369–378 Struzynska L, Dabrowska-Bouta B, Koza K, Sulkowski G (2007) Inflammation-like glial response in lead-exposed immature rat brain. Toxicol Sci 95:156–162 Sugama S, Fujita M, Hashimoto M, Conti B (2007) Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18. Neuroscience 146:1388–1399 Taga T, Fukuda S (2005) Role of IL-6 in the neural stem cell differentiation. Clin Rev Allergy Immunol 28:249–256 Tiffany-Castiglioni E, Sierra EM, Wu JN, Rowles TK (1989) Lead toxicity in neuroglia. Neurotoxicology 10:417–443 Van Wagoner NJ, Benveniste EN (1999) Interleukin-6 expression and regulation in astrocytes. J Neuroimmunol 100:124–139 382 J. Kasten-Jolly and D.A. Lawrence Van Wagoner NJ, Choi C, Repovic P, Benveniste EN (2000) Oncostatin M regulation of interleukin-6 expression in astrocytes: biphasic regulation involving the mitogen-activated protein kinases ERK1/2 and p38. J Neurochem 75:563–575 Weisskopf MG, Hu H, Sparrow D, Lenkinski RE, Wright RO (2007) Proton magnetic reso- nance spectroscopic evidence of glial effects of cumulative lead exposure in the adult human hippocampus. Environ Health Perspect 115:519–523 White LD, Cory-Slechta DA, Gilbert ME, Tiffany-Castiglioni E, Zawia NH, Virgolini M, Rossi- George A, Lasley SM, Qian YC, Basha MR (2007) New and evolving concepts in the neurotoxicology of lead. Toxicol Appl Pharmacol 225:1–27 Woiciechowsky C, Schoning B, Daberkow N, Asche K, Stoltenburg G, Lanksch WR, Volk H- D (1999) Brain-IL-1β induces local inflammation but systemic anti-inflammatory response through stimulation of both hypothalamic-pituitary-adrenal axis and sympathetic nervous system. Brain Res 816:563–571 Wong M-L, Bongiorno PB, Rettori V, McCann SM, Lici J (1997) Interleukin (IL) 1 β, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in central nervous system and anterior pituitary during systemic inflammation with pathophysiological implications. Proc Natl Acad Sci USA 94:227–232 Xiao B-G, Link H (1999) Is there a balance between microglia and astrocytes in regulating Th1/Th2-cell responses and neuropathologies? Trends Immunol 20:477–479 Yabe T, Sanagi T, Schwartz JP, Yamada H (2005) Pigment epithelium-derived factor induces pro- inflammatory genes in neonatal astrocytes through activation of NF-κB and CREB. GLIA 50:223–234 Zawia NH, Sharan R, Brydie M, Oyama T, Crumpton T (1998) Sp1 as a target site for metal- induced perturbation of transcriptional regulation of developmental brain gene expression. Dev Brain Res 107:291–298 Zhang J, Rivest S (2001) Anti-inflammatory effects of prostaglanding E 2 in the central nervous system in response to brain injury and circulating lipopolysaccharide. J Neurochem 76:855–864 Zipp F, Aktas O (2006) The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 29:518–527 Neurochemistry of Autism Timothy D. Folsom and S. Hossein Fatemi Abstract Autism is a neurodevelopmental disorder characterized by presence of social deficits, language abnormalities, stereotypies, and repetitive behavior. Brain pathology is extensive, suggesting widespread dysfunction of neurotransmitter sys- tems. Genetic, biochemical, and gene association studies have shown that a number of neurotransmitters including serotonin, dopamine, oxytocin, GABA and gluta- mate, and acetylcholine contribute to the pathology of autism. Pharmacological treatment of autism has focused on reduction of symptoms and atypical antipsy- chotics, antidepressants, mood stabilizers, and anticonvulsants have been shown to successfully reduce many symptoms of autism. In this review we discuss the contri- butions of neurotransmitter systems to the pathology of autism and pharmacological treatment of autistic symptoms associated with neurochemical dysfunction. Keywords Serotonin · GABA · Neurotransmitter · Neuropeptide · Pharmacotherapy · Genes Contents 1 Introduction 384 2 Serotonin 384 3 Dopamine 386 4 Acetylcholine 387 5 GABA and Glutamate 388 6 Oxytocin 389 7 Reelin in Autism 390 8 Conclusion 391 References 391 S.H. Fatemi (B) Division of Neuroscience Research, Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA e-mail: fatem002@umn.edu 383 J.P. Blass (ed.), Neurochemical Mechanisms in Disease, Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_13, C Springer Science+Business Media, LLC 2011 384 T.D. Folsom and S.H. Fatemi 1 Introduction Autism is a debilitating neurodevelopmental disorder with heritability of >90% (Bailey et al., 1996) and characterized by presence of social deficits, language abnormalities, stereotypies, and repetitive behavior (APA, 1994). There is perva- sive brain pathology encompassing different neurotransmitters and brain proteins (Bauman and Kemper, 1994, 2005; Acosta and Pearl, 2003; Palmen et al., 2004). Biochemical reports show involvement of several genes and proteins involved with neurotransmission implicating the GABAergic system (Blatt et al., 2001; Fatemi et al., 2002a, 2009a, b; Fatemi, 2008), cholinergic system (Perry et al., 2001;Lee et al., 2002), serotonergic system (Anderson, 2005), dopaminergic system (Gillberg et al., 1983; Gillberg and Svennerholm, 1987; de Krom et al., 2008), and the neuropeptide oxytocin (Waterhouse et al., 1996; Modahl et al., 1998) with the neu- ropathology of autism. Pharmacotherapy has focused on reduction of symptoms of autism including aggression, hyperactivity, self-injury, repetitive behavior, and anx- iety. Antipsychotics, antidepressants, mood stabilizers, and anticonvulsants, among other drugs have been shown to successfully reduce autistic symptoms. In the cur- rent review, we examine the possible contributions of the serotonin, dopamine, acetylcholine, GABA and glutamate, and oxytocin to the pathology of autism and pharmacological treatment strategies that have shown efficacy in reducing symptoms of autism. 2 Serotonin Serotonin (5-hydroxytrypamine) is an indolamine that is derived from tryptophan. A depletion in dietary tryptophan is known to lead to a worsening of autistic symp- toms (McDougle et al., 1996a). Serotonin regulates a host of functions including mood, body temperature, arousal, hormone release, and eating (reviewed by Berger et al., 2009). In the mature brain, serotonin acts as a neurotransmitter, in the devel- oping brain serotonin contributes to the development of serotonergic neurons and brain regions targeted by serotonergic neurons such as the prefrontal cortex (PFC) and hippocampus (Whitaker-Azmitia, 2001). Increased serotonin levels during early development may lead to a number of consequences contributing to brain pathology in autism (Whitaker-Azmita, 2005). Studies have shown that in utero exposure to drugs such as cocaine, that increase serotonin levels, result in higher rates of autism (Davis et al., 1992; Kramer et al., 1994). Conversely, low serotonin may also have negative effects on development and pose a risk factor for autism. Studies using an animal model have shown that when pregnant rats were treated with serotonin depletors it led to altered hippocampal and cortical development (Butkevich et al., 2003), abnormalities in levels of serotonin receptors in brain (Whitaker-Azmita et al., 1987), and behavioral abnormalities including passive avoidance (Shemer . chemotaxis in astroglia by up-regulating CXCR4 cell surface expression. J Biol Chem 277:39801–39808 Pahan K, Khan M, Singh I (2000) Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced. by antihistamine drugs in the developing mouse brain. Pediatr Res 50:222–230 Pinteaux E, Inoue W, Schmidt L, Molina-Holgado F, Rothwell NJ, Luheshi GN (2007) Leptin induces interleukin-1β release. plasma levels of interleukin-1, interleukin-6 and α-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral in ammation or signals from the brain. J Neuroimmunol 103:97–102 Lindahl LS,