Scientific Online Resource System

Biomedical Reviews

Ethanol Consumption and Innate Neuroimmunity

Stefania Ciafrè, Valentina Carito, Paola Tirassa, Giampiero Ferraguti, Maria Luisa Attilia, Paola Ciolli, Marisa Patrizia Messina, Mauro Ceccanti, Marco Fiore


Emerging researches from human and animal models have shown the role of ethanol in innate immune system modulation, particularly in the central nervous system. The activation of receptors of the innate immunity, Toll-like receptors and nucleotide- binding oligomerization domain-like (NOD-like) receptors, triggers the signaling pathways that bring to the production of pro-inflammatory cytokines and chemokines, which, in turn, provokes neuroinflammation and neural damage. The neuroimmune system response to ethanol intake, in specific brain regions such as amygdala, hippocampus and frontal cortex, is involved in addiction and in behavioural deficits observed in alcoholism. In murine models, the knockout for Toll-like or NODlike receptors abolishes most of the effects of ethanol on the immune system and preserves these mice from neural damage, neuroinflammation and alcohol dependence. Molecular targeting of immune system pathways is a new and promising area of research for the discovery of new biomarkers for neuroinflammation and for the development of novel pharmacotherapies in order to treat neurological and behavioural consequences of ethanol addiction. Biomed Rev 2017; 28: 49-61.

Keywords: ethanol addiction, neuroinflammation, neuroimmunity, Toll-like receptors, NOD-like receptors, inflammasomes

Full Text


Crews FT, Vetreno RP. Mechanisms of neuroimmune gene induction in alcoholism. Psychopharmacology (Berl) 2016;233:1543-1557. DOI:10.1007/s00213-015-3906-1

Szabo G, Saha B. Alcohol`s effect on host defense. Alcohol Res Curr Rev 2015;37:159-170.

Mandrekar P, Szabo G. Signalling pathways in alcoholinduced liver inflammation. J Hepatol 2009;50:1258-1266. DOI:10.1016/j.jhep.2009.03.007

Ferrier L, Bérard F, Debrauwer L, Chabo C, Langella P, Buéno L, et al. Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. Am J Pathol 2006;168:1148-1154. DOI:10.2353/ajpath.2006.050617

Szabo G, Mandrekar P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin

Exp Res 2009;33:220-232. DOI:10.1111/j.1530-0277.2008.00842.x

Vetreno RP, Qin L, Crews FT. Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking. Neurobiol Dis 2013; 59:52-62. DOI:10.1016/j.nbd.2013.07.002

Dantzer R, O`Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:46-56. DOI:10.1038/nrn2297

Watkins LR, Maier SF, Goehler LE. Cytokine-to-brain communication: a review & analysis of alternative mechanisms. Life Sci 1995;57:1011-1026. DOI: 10.1016/0024-3205(95)02047-M

Banks WA, Erickson MA. The blood-brain barrier and immune function and dysfunction. Neurobiol Dis 2010;37:26-32. DOI:10.1016/j.nbd.2009.07.031

Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong J-S, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007;55:453-62. DOI: 10.1002/glia.20467

Kreutzberg GW. Microglia, the first line of defence in brain pathologies. Arzneimittelforschung 1995; 45:357-60.

Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 1995;20:269-87. [DOI: 10.1016/0165-0173(94)00015-H]

Davis EJ, Foster TD, Thomas WE. Cellular forms and functions of brain microglia. Brain Res Bull 1994;34:73-78. DOI:10.1016/0361-9230(94)90189-9]

Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, et al. Role of microglia in central nervous system infections. Clin Microbiol Rev 2004;17:942-964, table of contents. DOI: 10.1128/CMR.17.4.942-964.2004

Eggen BJL, Raj D, Hanisch U-K, Boddeke HWGM. Microglial phenotype and adaptation. J Neuroimmune Pharmacol 2013;8:807-823. DOI:10.1007/s11481-013-9490-4

Ferrer I, Bernet E, Soriano E, del Rio T, Fonseca M. Naturally occurring cell death in the cerebral cortex of the rat and removal of dead cells by transitory phagocytes. Neuroscience 1990;39:451-458.

Aloisi F. Immune function of microglia. Glia 2001;36:165-79. [DOI: 10.1002/glia.1106]

Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol (Berl) 2010;119:89-105. DOI:10.1007/s00401-009-0622-0

Graeber MB. Changing face of microglia. Science 2010;330:783-8. DOI: 10.1126/science.1190929

Aschner M, Sonnewald U, Tan KH. Astrocyte modulation of neurotoxic injury. Brain Pathol Zurich Switz 2002;12:475-481. DOI: 10.1111/j.1750-3639.2002.tb00465.x

Aschner M. Astrocytes as mediators of immune and inflammatory responses in the CNS. Neurotoxicology 1998;19:269-281.

Medzhitov R, Preston-Hurlburt P, Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997;388:394-397. DOI:10.1038/41131

Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001;2:675-680. DOI:10.1038/90609

Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007;81:1-5. DOI:10.1189/jlb.0306164

Ibrahim ZA, Armour CL, Phipps S, Sukkar MB. RAGE and TLRs: relatives, friends or neighbours? Mol Immunol 2013;56:739-744. DOI:10.1016/j.molimm.2013.07.008

El Mezayen R, El Gazzar M, Seeds MC, McCall CE, Dreskin SC, Nicolls MR. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett 2007;111:36-44. DOI:10.1016/j.imlet.2007.04.011

Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 2010;140:918-934. DOI:10.1016/j.cell.2010.02.016

Vallés SL, Blanco AM, Pascual M, Guerri C. Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol Zurich Switz 2004;14:365-371. DOI: 10.1111/j.1750-3639.2004.tb00079.x

Qin L, He J, Hanes RN, Pluzarev O, Hong J-S, Crews FT. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflam 2008;5:10. DOI:10.1186/1742-2094-5-10

Blanco AM, Vallés SL, Pascual M, Guerri C. Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes. J Immunol 2005;175:6893- 6899. DOI:10.4049/jimmunol.175.10.6893

Blanco AM, Perez-Arago A, Fernandez-Lizarbe S, Guerri C. Ethanol mimics ligand-mediated activation and endocytosis of IL-1RI/TLR4 receptors via lipid rafts caveolae in astroglial cells. J Neurochem 2008;106:625-639. DOI:10.1111/j.1471-4159.2008.05425.x

Guo S, Yang C, Diao B, Huang X, Jin M, Chen L, et al. The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis. PLoS 2015;11:e1005155. DOI:10.1371/journal.ppat.1005155

Pascual-Lucas M, Fernandez-Lizarbe S, Montesinos J, Guerri C. LPS or ethanol triggers clathrin- and rafts/ caveolae-dependent endocytosis of TLR4 in cortical astrocytes. J Neurochem 2014; 129:448-62. DOI:10.1111/jnc.12639

Fernandez-Lizarbe S, Pascual M, Guerri C. Critical role of TLR4 response in the activation of microglia induced by ethanol. J Immunol Baltim Md 2009;183:4733-44. DOI: 10.4049/jimmunol.0803590

Alfonso-Loeches S, Ureña-Peralta JR, Morillo-Bargues MJ, Oliver-De La Cruz J, Guerri C. Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci 2014;8:216. DOI:10.3389/fncel.2014.00216

Alfonso-Loeches S, Guerri C. Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain. Crit Rev Clin Lab Sci 2011;48:19-47. DOI: 10.3109/10408363.2011.580567

Alfonso-Loeches S, Pascual M, Gómez-Pinedo U, Pascual-Lucas M, Renau-Piqueras J, Guerri C. Toll-like receptor 4 participates in the myelin disruptions associated with chronic alcohol abuse. Glia 2012;60:948-64. DOI:10.1002/glia.22327

Alfonso-Loeches S, Pascual M, Guerri C. Gender differences in alcohol-induced neurotoxicity and brain damage. Toxicology 2013;311:27-34. DOI:10.1016/j.tox.2013.03.001

Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci J Soc Neurosci 2010;30:8285-95. DOI:10.1523/JNEUROSCI.0976-10.2010

Alfonso-Loeches S, Ureña-Peralta J, Morillo-Bargues MJ, Gómez-Pinedo U, Guerri C. Ethanol-Induced TLR4/ NLRP3 Neuroinflammatory Response in Microglial Cells Promotes Leukocyte Infiltration Across the BBB. Neurochem Res 2016;41:193-209. DOI:10.1007/s11064-015-1760-5

Pla A, Pascual M, Renau-Piqueras J, Guerri C. TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain. Cell Death Dis 2014;5:e1066. [doi:10.1038/cddis.2014.46.]

Zou J, Vetreno RP, Crews FT. ATP-P2X7 receptor signaling controls basal and TNFα-stimulated glial cell proliferation. Glia 2012;60:661-73. [DOI: 10.1002/glia.22302]

Montesinos J, Alfonso-Loeches S, Guerri C. Impact of the Innate Immune Response in the Actions of Ethanol on the Central Nervous System. Alcohol Clin Exp Res 2016;40:2260-70. [DOI:10.1111/acer.13208]

Montesinos J, Pascual M, Rodríguez-Arias M, Miñarro J, Guerri C. Involvement of TLR4 in the long-term epigenetic changes, rewarding and anxiety effects induced by intermittent ethanol treatment in adolescence. Brain Behav Immun 2016;53:159-171. DOI:10.1016/j.bbi.2015.12.006

Vetreno RP, Crews FT. Current hypotheses on the mechanisms of alcoholism. Handb Clin Neurol 2014;125:477- 97. DOI:10.1016/B978-0-444-62619-6.00027-646.

Crews FT, Vetreno RP. Neuroimmune basis of alcoholic brain damage. Int Rev Neurobiol 2014; 118:315-57. DOI:10.1016/B978-0-12-801284-0.00010-5

Rubio-Araiz A, Porcu F, Pérez-Hernández M, García-Gutiérrez MS, Aracil-Fernández MA, Gutierrez-López MD, et al. Disruption of blood-brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model. Addict Biol 2017; 22:1103-16. DOI:10.1111/adb.12376

Pruett SB, Zheng Q, Fan R, Matthews K, Schwab C. Ethanol suppresses cytokine responses induced through Toll-like receptors as well as innate resistance to Escherichia coli in a mouse model for binge drinking. Alcohol Fayettev N 2004;33:147-55. DOI: 10.1016/j.alcohol.2004.08.001

Kuwata H, Watanabe Y, Miyoshi H, Yamamoto M, Kaisho T, Takeda K, et al. IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Blood 2003; 102:4123-4129. DOI: 10.1182/blood-2003-04-1228

Deak T, Okrainets A, Doremus-Fitzwater TL. Mechanisms of stress-dependent neuroinflammation and their implications for understanding consequences of alcohol exposure. Neural-Immune Interact. Brain Funct. Alcohol Relat. Disord., Springer; 2013, p. 133-66.

Barr T, Helms C, Grant K, Messaoudi I. Opposing effects of alcohol on the immune system. Prog Neuropsychopharmacol Biol Psychiatry 2016;65:242-51. DOI: 10.1016/j.pnpbp.2015.09.001

Mandrekar P, Bala S, Catalano D, Kodys K, Szabo G. The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAKM in human monocytes. J Immunol Baltim Md 1950 2009;183:1320-7. DOI:10.4049/jimmunol.0803206

Laso FJ, Vaquero JM, Almeida J, Marcos M, Orfao A. Production of inflammatory cytokines by peripheral blood monocytes in chronic alcoholism: relationship with ethanol intake and liver disease. Cytometry B Clin Cytom 2007;72:408-15. DOI:10.1002/cyto.b.20169

Burke HM, Davis MC, Otte C, Mohr DC. Depression and cortisol responses to psychological stress: a metaanalysis. Psychoneuroendocrinology 2005; 30:846-56. DOI: 10.1016/j.psyneuen.2005.02.010

Sinha R, Fox HC, Hong K-IA, Hansen J, Tuit K, Kreek MJ. Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes. Arch Gen Psychiatry 2011;68:942-52. DOI:10.1001/archgenpsychiatry.2011.49

Breese GR, Overstreet DH, Knapp DJ, Navarro M. Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF1- and benzodiazepine-receptor antagonists and a 5-HT1a-receptor agonist. Am Coll Neuropsychopharmacol 2005;30:1662-1669. DOI: 10.1038/sj.npp.1300706

Alonso R, Griebel G, Pavone G, Stemmelin J, Le Fur G, Soubrié P. Blockade of CRF1 or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol Psychiatry 2004;9:278-286, 224. DOI:10.1038/

Badawy AA-B, Doughrty DM, Marsh-Richard DM, Steptoe A. Activation of liver tryptophan pyrrolase mediates the decrease in tryptophan availability to the brain after acute alcohol consumption by normal subjects. Alcohol Alcohol Oxf 2009;44:267-271. DOI:10.1093/alcalc/


Branchey L, Branchey M, Shaw S, Lieber CS. Relationship between changes in plasma amino acids and depression in alcoholic patients. Am J Psychiatry 1984;141:1212-1215. DOI: 10.1176/ajp.141.10.1212

Dantzer R, O`Connor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 2011;36:426-36. DOI: 10.1016/j.psyneuen.2010.09.012

O`Connor JC, André C, Wang Y, Lawson MA, Szegedi SS, Lestage J, et al. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci Off J Soc Neurosci 2009;29:4200-9. DOI:10.1523/JNEUROSCI.5032-08.2009

Cui C, Grandison L, Noronha A. Neural-immune interactions in brain function and alcohol related disorders. Springer Science & Business Media; 2012.

Maes M, Bosmans E, Suy E, Vandervorst C, De Jonckheere C, Raus J. Immune disturbances during major depression: upregulated expression of interleukin-2 receptors. Neuropsychobiology 1990;24:115-120.

Smith RS. The macrophage theory of depression. Med Hypotheses 1991;35:298-306.

Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, et al. The inflammatory and neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Me- tab Brain Dis 2009;24:27-53. DOI:10.1007/s11011-008-9118-1

Crews FT, Vetreno RP. Addiction, adolescence, and innate immune gene induction. Front Psychiatry 2011;2:19. DOI:10.3389/fpsyt.2011.00019

Ceccanti M, Coriale G, Hamilton D, Carito V, Coccurello R, Scalese B, et al. Virtual Morris task responses in individuals in an abstinence phase from alcohol. Can J Physiol Pharmacol 2017. DOI: 10.1139/cjpp-2017-0013

Ceccanti M, Hamilton D, Coriale G, Carito V, Aloe L, Chaldakov G, et al. Spatial learning in men undergoing alcohol detoxification. Physiol Behav 2015;149:324-30. DOI: 10.1016/j.physbeh.2015.06.034

Zhao C, Teng EM, Summers RG, Ming G-L, Gage FH. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci Off J Soc Neurosci 2006; 26:3-11. [doi:10.1523/JNEUROSCI.3648-05.2006.]

Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965;124:319-35.

Stanton PK. LTD, LTP, and the sliding threshold for longterm synaptic plasticity. Hippocampus 1996;6:35-42. DOI:10.1002/(SICI)1098-1063(1996)6:1<35::AIDHIPO7>3.0.CO;2-6

Maggio N, Shavit-Stein E, Dori A, Blatt I, Chapman J. Prolonged systemic inflammation persistently modifies synaptic plasticity in the hippocampus: modulation by the stress hormones. Front Mol Neurosci 2013;6:46. DOI:10.3389/fnmol.2013.00046

Zou J, Crews F. Induction of innate immune gene expression cascades in brain slice cultures by ethanol: key role of NF-κB and proinflammatory cytokines. Alcohol Clin Exp Res 2010;34:777-789. DOI:10.1111/j.1530-0277.2010.01150.x

Nixon K, Crews FT. Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. J

Neurochem 2002;83:1087-93. DOI: 10.1046/j.1471-4159.2002.01214.x

Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, et al. Cytokines and alcohol. Alcohol Clin Exp Res 2006;30:720-30. DOI:10.1111/j.1530-0277.2006.00084.x

McClain JA, Morris SA, Deeny MA, Marshall SA, Hayes DM, Kiser ZM, et al. Adolescent binge alcohol exposure induces long-lasting partial activation of microglia. Brain Behav Immun 2011;25 Suppl 1:S120-128. DOI:10.1016/j.bbi.2011.01.006

Gonzalez-Perez O, Ramos-Remus C, Garcia-Estrada J, Luquin S. Prednisone induces anxiety and glial cerebral changes in rats. J Rheumatol 2001;28:2529-2534.

Blednov YA, Bergeson SE, Walker D, Ferreira VMM, Kuziel WA, Harris RA. Perturbation of chemokine networks by gene deletion alters the reinforcing actions of ethanol. Behav Brain Res 2005;165:110-125. DOI:10.1016/j.bbr.2005.06.026

June HL, Liu J, Warnock KT, Bell KA, Balan I, Bollino D, et al. CRF-amplified neuronal TLR4/MCP-1 signaling regulates alcohol self-administration. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 2015;40:1549-1559. DOI:10.1038/npp.2015.4

Montesinos J, Pascual M, Pla A, Maldonado C, Rodríguez-Arias M, Miñarro J, et al. TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment. Brain Behav Immun 2015;45:233-44. DOI: 10.1016/j.bbi.2014.11.015

Pascual M, Baliño P, Alfonso-Loeches S, Aragón CMG, Guerri C. Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage. Brain Behav Immun 2011; 25 (Suppl 1):S80-91. DOI:10.1016/j.bbi.2011.02.012

Blednov YA, Ponomarev I, Geil C, Bergeson S, Koob GF, Harris RA. Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addict Biol 2012;17:108-20. DOI:10.1111/j.1369-1600.2010.00284.x

Achur RN, Freeman WM, Vrana KE. Circulating cytokines as biomarkers of alcohol abuse and alcoholism. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol 2010;5:83-91. DOI: 10.1007/s11481-009-9185-z

Kissack JC, Bishop J, Roper AL. Ethylglucuronide as a biomarker for ethanol detection. Pharmacotherapy 2008;28:769-781. DOI:10.1592/phco.28.6.769

Ferraguti G, Ciolli P, Carito V, Battagliese G, Mancinelli R, Ciafrè S, et al. Ethylglucuronide in the urine as a marker of alcohol consumption during pregnancy: Comparison with four alcohol screening questionnaires. Toxicol Lett 2017;275:49-56. DOI:10.1016/j.toxlet.2017.04.016

Taracha E, Habrat B, Woźniak P, Walkowiak J, Szukalski B. The activity of beta-hexosaminidase (uHex) and gamma-glutamyl-transferase (uGGT) in urine as non-invasive markers of chronic alcohol abuse: I. Alcohol-dependent subjects. World J Biol Psychiatry Off J World Fed Soc Biol Psychiatry 2001;2:184-9. DOI: 10.3109/15622970109026807

Niemelä O. Biomarker-based approaches for assessing alcohol use disorders. Int J Environ Res Public Health 2016;13:166. DOI:10.3390/ijerph13020166

Koch H, Meerkerk G-J, Zaat JOM, Ham MF, Scholten RJPM, Assendelft WJJ. Accuracy of carbohydrate-deficient transferrin in the detection of excessive alcohol consumption: a systematic review. Alcohol Alcohol Oxf Oxfs 2004;39:75-85.

Golka K, Wiese A. Carbohydrate-deficient transferrin (CDT)--a biomarker for long-term alcohol consumption. J Toxicol Environ Health B Crit Rev 2004;7:319-337. DOI: 10.1080/10937400490432400

Helander A, Eriksson CJP, WHO/ISBRA Study on State and Trait Markers ofAlcohol Use and Dependence Investigators. Laboratory tests for acute alcohol consumption: results of the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence. Alcohol Clin Exp Res 2002;26:1070-1077. DOI: 10.1111/j.1530-0277.2002.tb02641.x

Comasco E, Nordquist N, Leppert J, Oreland L, Kronstrand R, Alling C, et al. Adolescent alcohol consumption: biomarkers PEth and FAEE in relation to interview and questionnaire data. J Stud Alcohol Drugs 2009;70:797-804. DOI: 10.15288/jsad.2009.70.797

Björkqvist M, Ohlsson M, Minthon L, Hansson O. Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer`s disease. PloS One 2012;7:e29868. DOI: 10.1371/journal.pone.0029868

An L, Wang X, Cederbaum AI. Cytokines in alcoholic liver disease. Arch Toxicol 2012;86:1337-1348. DOI: 10.1007/s00204-012-0814-6

Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM, et al. Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. Clin Exp Immunol 2008;151:42-50. DOI:10.1111/j.1365-2249.2007.03545.x

Gonzalez-Quintela A, Garrido M, Gude F, Campos J, Linneberg A, Lojo S, et al. Sensitization to crossreactive carbohydrate determinants in relation to alcohol consumption. Clin Exp Allergy 2008;38:152-60. DOI: 10.1111/j.1365-2222.2007.02863.x

Carito V, Ceccanti M, Ferraguti G, Coccurello R, Ciafrè S, Tirassa P, et al. NGF and BDNF alterations by prenatal alcohol exposure. Curr Neuropharmacol 2017. DOI: 10.2174/1570159X15666170825101308

Ceccanti M, De Nicolo S, Mancinelli R, Chaldakov G, Carito V, Ceccanti M, et al. NGF and BDNF longterm variations in the thyroid, testis and adrenal glands of a mouse model of fetal alcohol spectrum disorders. Ann Ist Super Sanita 2013;49:383-90. DOI: 10.4415/ann_13_04_11

Ceccanti M, Mancinelli R, Tirassa P, Laviola G, Rossi S, Romeo M, et al. Early exposure to ethanol or red wine and long-lasting effects in aged mice. A study on nerve growth factor, brain-derived neurotrophic factor, hepatocyte growth factor, and vascular endothelial growth factor. Neurobiol Aging 2012;33:359-367. DOI: 10.1016/j.neurobiolaging.2010.03.005

Ceccanti M, Carito V, Vitali M, Iannuzzi S, Tarani L, De Nicolò S, et al. Serum BDNF and NGF modulation by olive polyphenols in alcoholics during withdrawal. J Alcohol Drug Depend 2015;3:1-6. DOI:10.4172/2329-6488.1000214]

Ceccanti M, Coccurello R, Carito V, Ciafrè S, Ferraguti G, Giacovazzo G, et al. Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring. Addict Biol 2016;21:776-787. DOI:10.1111/adb.12255

De Nicolo S, Tarani L, Ceccanti M, Maldini M, Natella F, Vania A, et al. Effects of olive polyphenols administration on nerve growth factor and brain-derived neurotrophic factor in the mouse brain. Nutrition 2013;29:681-687. DOI: 10.1016/j.nut.2012.11.007

Fiore M, Mancinelli R, Aloe L, Laviola G, Sornelli F, Vitali M, et al. Hepatocyte growth factor, vascular endothelial growth factor, glial cell-derived neurotrophic factor and nerve growth factor are differentially affected by early chronic ethanol or red wine intake. Toxicol Lett 2009; 188:208-13. DOI: 10.1016/j.toxlet.2009.04.013

Aloe L. Alcohol intake during prenatal life affects neuroimmune mediators and brain neurogenesis. Ann Ist Super Sanita 2006;42:17-21.

De Simone R, Aloe L. Influence of ethanol consumption on brain nerve growth factor and its target cells in developing and adult rodents. Ann Ist Super Sanita 1993;29:179-183.

Aloe L, Bracci-Laudiero L, Tirassa P. The effect of chronic ethanol intake on brain NGF level and on NGF-target tissues of adult mice. Drug Alcohol Depend 1993;31:159-167. DOI: 10.1016/0376-8716(93)90068-2 Aloe L, Tirassa P. The effect of long-term alcohol intake on brain NGF-target cells of aged rats. Alcohol 1992;9:299-304. DOI:10.1016/0741-8329(92)90070-Q

Aloe L, Tuveri MA, Guerra G, Pinna L, Tirassa P, Micera A, et al. Changes in human plasma nerve growth factor level after chronic alcohol consumption and withdrawal. Alcohol Clin Exp Res 1996;20:462-465. DOI: 10.1111/j.1530-0277.1996.tb01076.x

Vuorela P, Sarkola T, Alfthan H, Halmesmäki E. Hepatocyte growth factor, epidermal growth factor, and placenta growth factor concentrations in peripheral blood of pregnant women with alcohol abuse. Alcohol Clin Exp Res 2002;26:682-687. DOI: 10.1111/j.1530-0277.2002.tb02591.x

Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG, et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci USA 2009;106:3507-3512. DOI:10.1073/pnas.0805854106

Kocerha J, Kauppinen S, Wahlestedt C. microRNAs in CNS disorders. Neuromolecular Med 2009;11:162-172. DOI:10.1007/s12017-009-8066-1

Lippai D, Bala S, Petrasek J, Csak T, Levin I, Kurt-Jones EA, et al. Alcohol-induced IL-1β in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation. J Leukoc Biol 2013;94:171-82. DOI:10.1189/jlb.1212659

Zhang Y, Wei G, Di Z, Zhao Q. miR-339-5p inhibits alcohol-induced brain inflammation through regulating NF-κB pathway. Biochem Biophys Res Commun 2014;452:450-456. DOI: 10.1016/j.bbrc.2014.08.092

Vetreno RP, Yaxley R, Paniagua B, Johnson GA, Crews FT. Adult rat cortical thickness changes across age and following adolescent intermittent ethanol treatment. Addict Biol 2017;22:712-723. DOI: 10.1111/adb

Risher ML, Sexton HG, Risher WC, Wilson WA, Fleming RL, Madison RD, et al. Adolescent intermittent alcohol exposure: dysregulation of thrombospondins and synapse formation are associated with decreased neuronal density in the adult hippocampus. Alcohol Clin Exp Res

;39:2403-2413. DOI: 10.1111/acer.12913

Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 2000;24:417-463.403-2413. [

Spear LP. Adolescents and alcohol. Curr Dir Psychol Sci 2013;22:152-157. DOI: 10.1177/0963721412472192

Luna B, Marek S, Larsen B, Tervo-Clemmens B, Chahal R. An integrative model of the maturation of cognitive control. Annu Rev Neurosci 2015;38:151-170. DOI: 10.1146/annurev-neuro-071714-034054

Grant BF. The impact of a family history of alcoholism on the relationship between age at onset of alcohol use and DSM-IV alcohol dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. Alcohol Health Res World 1998;22: 144-147.

Gao F, Liu Z, Ren W, Jiang W. Acute lipopolysaccharide exposure facilitates epileptiform activity via enhanced excitatory synaptic transmission and neuronal excitability in vitro. Neuropsychiatr Dis Treat 2014;10:1489-1495. DOI: 10.2147/NDT.S65695

Guerri C, Pascual M. Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence. Alcohol 2010;44:15-26. DOI: 10.1016/j.alcohol.2009.10.003

Pascual M, Blanco AM, Cauli O, Minarro J, Guerri C. Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci 2007;25:541-550. DOI: 10.1111/j.1460-9568.2006.05298.x

Ward RJ, Colivicchi MA, Allen R, Schol F, Lallemand F, de Witte P, Ballini C, Corte LD, Dexter D. Neuro-inflammation induced in the hippocampus of `binge drinking` rats may be mediated by elevated extracellular glutamate content. J Neurochem 2009;111:1119-1128. DOI: 10.1111/j.1471-4159.2009.06389.x

Vetreno RP, Crews FT. Adolescent binge drinking increases expression of the danger signal receptor agonist HMGB1 and Toll-like receptors in the adult prefrontal cortex. Neuroscience 2012;226:475-488. [doi: 10.1016/j.neuroscience.2012.08.046]

Zou JY, Crews FT. Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling. PLoS One 2014;9:e87915. DOI: 10.1371/journal.pone.0087915

Cantacorps L, Alfonso-Loeches S, Moscoso-Castro M, Cuitavi J, Gracia-Rubio I, López-Arnau R, et al. Maternal alcohol binge drinking induces persistent neuroinflammation associated with myelin damage and behavioural dysfunctions in offspring mice. Neuropharmacology 2017; 123:368-384. DOI: 10.1016/j.neuropharm.2017.05.034

Agrawal RG, Hewetson A, George CM, Syapin PJ, Bergeson SE Minocycline reduces ethanol drinking. Brain Behav Immun 2011;25(Suppl 1): S165-S169. DOI: 10.1016/j.bbi.2011.03.002

Wu Y, Lousberg EL, Moldenhauer LM, Hayball JD, Robertson SA, Coller JK, Watkins LR, Somogyi AA, Hutchinson MR. Attenuation of microglial and IL-1 signaling protects mice from acute alcohol-induced sedation and/ or motor impairment. Brain Behav Immun 2011;25(Suppl 1): S155-S164. DOI: 10.1016/j.bbi.2011.01.012

Whitman BA, Knapp DJ, Werner DF, Crews FT, Breese GR. The cytokine mRNA increase induced by withdrawal from chronic ethanol in the sterile environment of brain is mediated by CRF and HMGB1 release. Alcohol Clin Exp Res 2012;37:2086-2097. DOI: 10.1111/acer.12189

Anton M, Alen F, Gomez de Heras R, Serrano A, Pavon FJ, Leza JC, et al. Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF-kB danger signaling in rat frontal cortex and depressive-like behavior induced by ethanol binge administration. Addict Biol 2017;22:724-741. DOI: 10.1111/adb.12365.

Carito V, Ceccanti M, Tarani L, Ferraguti G, Chaldakov GN, Fiore M. Neurotrophins` modulation by olive polyphenols. Curr Med Chem 2016;23:3189-3197. DOI: 10.2 174/0929867323666160627104022

Carito V, Ceccanti M, Cestari V, Natella F, Bello C, Coccurello R, Mancinelli R, Fiore M. Olive polyphenol effects in a mouse model of chronic ethanol addiction. Nutrition 2017;33:65-69. DOI: 10.1016/j.nut.2016.08.014.



Article Tools
Email this article (Login required)
About The Authors

Stefania Ciafrè
Institute of Translational Pharmacology, CNR, Rome Institute of Cell Biology and Neurobiology, IBCN-CNR, Rome

Valentina Carito
Institute of Cell Biology and Neurobiology, IBCN-CNR, Rome

Paola Tirassa
Institute of Cell Biology and Neurobiology, IBCN-CNR, Rome

Giampiero Ferraguti
Sapienza University, Rome

Department of Cellular Biotechnologies and Hematology

Maria Luisa Attilia
Sapienza University, Rome

Centro Riferimento Alcologico Regione Lazio

Paola Ciolli
Sapienza University, Rome

Department of Gynecology and Obstetric, and Urology

Marisa Patrizia Messina
Sapienza University, Rome

Centro Riferimento Alcologico Regione Lazio

Mauro Ceccanti
Sapienza University, Rome

Centro Riferimento Alcologico Regione Lazio

Marco Fiore
Institute of Cell Biology and Neurobiology, IBCN-CNR, Rome

Font Size