Does Brain Inflammation Mediate Pathological Outcomes in Epilepsy?

  • Karen S. Wilcox
  • Annamaria Vezzani
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 813)


Inflammation in the central nervous system (CNS) is associated with epilepsy and is characterized by the increased levels of a complex set of soluble molecules and their receptors in epileptogenic foci with profound neuromodulatory effects. These molecules activate receptor-mediated pathways in glia and neurons that contribute to hyperexcitability in neural networks that underlie seizure generation. As a consequence, exciting new opportunities now exist for novel therapies targeting the various components of the immune system and the associated inflammatory mediators, especially the IL-1β system. This review summarizes recent findings that increased our understanding of the role of inflammation in reducing seizure threshold, contributing to seizure generation, and participating in epileptogenesis. We will discuss preclinical studies supporting the hypothesis that pharmacological inhibition of specific proinflammatory signalings may be useful to treat drug-resistant seizures in human epilepsy, and possibly delay or arrest epileptogenesis.


Inflammation IL-1β TNF-α IL-6 Reactive astrogliosis 



A. Vezzani is very grateful to Phil Schwarzkroin for the intense and fruitful collaboration during the 8 years of shared editorial work for Epilepsia. During the time A.V. was serving as associated editor for basic science, she could fully appreciate P.S. extensive and deep scientific knowledge, his patience, constructive criticism, support and commitment. She thanks Phil, in particular, for his willingness to share responsibility and decisions as well as complaints and rewards, and for the very educational and formative time.

K.S. Wilcox would like to acknowledge the kind support Phil Schwartzkroin has demonstrated over the years. While she never had the opportunity to work with him, he was always interested in her work, encouraged her to speak out at meetings, to get involved in the American Epilepsy Society, and provided a welcoming environment for someone entering the field of epilepsy. He is a mentor to all.

Other Acknowledgements

This work was supported by National Institutes of Health Grants NS 078331 (KSW), NS065434 (KSW), and the Margolis Foundation (KSW) and Ministero della salute Grant N. RF-2009-1506142 (AV).


  1. 1.
    Akin D, Ravizza T, Maroso M, Carcak N, Eryigit T, Vanzulli I et al (2011) IL-1beta is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence. Neurobiol Dis 44(3):259–269PubMedGoogle Scholar
  2. 2.
    Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22(5):208–215PubMedGoogle Scholar
  3. 3.
    Aronica E, Ravizza T, Zurolo E, Vezzani A (2012) Astrocyte immune responses in epilepsy. Glia 60(8):1258–1268PubMedGoogle Scholar
  4. 4.
    Aronica E, Sandau US, Iyer A, Boison D (2013) Glial adenosine kinase – a neuropathological marker of the epileptic brain. Neurochem Int 63:688–695PubMedGoogle Scholar
  5. 5.
    Auvin S, Mazarati A, Shin D, Sankar R (2010) Inflammation enhances epileptogenesis in the developing rat brain. Neurobiol Dis 40(1):303–310PubMedCentralPubMedGoogle Scholar
  6. 6.
    Auvin S, Shin D, Mazarati A, Sankar R (2010) Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA. Epilepsia 51(Suppl 3):34–38PubMedCentralPubMedGoogle Scholar
  7. 7.
    Balosso S, Maroso M, Sanchez-Alavez M, Ravizza T, Frasca A, Bartfai T et al (2008) A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain 131(Pt 12):3256–3265PubMedCentralPubMedGoogle Scholar
  8. 8.
    Balosso S, Ravizza T, Aronica E, Vezzani A (2013) The dual role of TNF-alpha and its receptors in seizures. Exp Neurol 247C:267–271Google Scholar
  9. 9.
    Balosso S, Ravizza T, Perego C, Peschon J, Campbell IL, De Simoni MG et al (2005) Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors. Ann Neurol 57(6):804–812PubMedGoogle Scholar
  10. 10.
    Bauer J, Vezzani A, Bien CG (2012) Epileptic encephalitis: the role of the innate and adaptive immune system. Brain Pathol 22(3):412–421PubMedGoogle Scholar
  11. 11.
    Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M et al (2002) Control of synaptic strength by glial TNFalpha. Science 295(5563):2282–2285PubMedGoogle Scholar
  12. 12.
    Bellinger FP, Madamba S, Siggins GR (1993) Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Res 628(1–2):227–234PubMedGoogle Scholar
  13. 13.
    Bien CG, Tiemeier H, Sassen R, Kuczaty S, Urbach H, von Lehe M et al (2013) Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins. Epilepsia 54(3):543–550PubMedGoogle Scholar
  14. 14.
    Bittner S, Simon OJ, Gobel K, Bien CG, Meuth SG, Wiendl H (2013) Rasmussen encephalitis treated with natalizumab. Neurology 81(4):395–397PubMedGoogle Scholar
  15. 15.
    Boison D (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 65(3):906–943PubMedCentralPubMedGoogle Scholar
  16. 16.
    Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M et al (2009) Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci 29(28):8927–8935PubMedCentralPubMedGoogle Scholar
  17. 17.
    Chen CJ, Ou YC, Chang CY, Pan HC, Liao SL, Chen SY et al (2012a) Glutamate released by Japanese encephalitis virus-infected microglia involves TNF-alpha signaling and contributes to neuronal death. Glia 60(3):487–501Google Scholar
  18. 18.
    Chen J, Tsai V, Parker WE, Aronica E, Baybis M, Crino PB (2012b) Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann Neurol 72(6):881–892Google Scholar
  19. 19.
    Collignon F, Wetjen NM, Cohen-Gadol AA, Cascino GD, Parisi J, Meyer FB et al (2006) Altered expression of connexin subtypes in mesial temporal lobe epilepsy in humans. J Neurosurg 105(1):77–87PubMedGoogle Scholar
  20. 20.
    Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60(8):1215–1226PubMedCentralPubMedGoogle Scholar
  21. 21.
    Cusick MF, Libbey JE, Patel DC, Doty DJ, Fujinami RS (2013) Infiltrating macrophages are key to the development of seizures following virus infection. J Virol 87(3):1849–1860PubMedCentralPubMedGoogle Scholar
  22. 22.
    David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D et al (2009) Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J Neurosci 29(34):10588–10599PubMedCentralPubMedGoogle Scholar
  23. 23.
    Davis CN, Tabarean I, Gaidarova S, Behrens MM, Bartfai T (2006) IL-1beta induces a MyD88-dependent and ceramide-mediated activation of Src in anterior hypothalamic neurons. J Neurochem 98(5):1379–1389PubMedGoogle Scholar
  24. 24.
    De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F et al (2000) Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci 12(7):2623–2633PubMedGoogle Scholar
  25. 25.
    Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA (2013) Glia and epilepsy: excitability and inflammation. Trends Neurosci 36(3):174–184PubMedGoogle Scholar
  26. 26.
    Diem R, Hobom M, Grotsch P, Kramer B, Bahr M (2003) Interleukin-1 beta protects neurons via the interleukin-1 (IL-1) receptor-mediated Akt pathway and by IL-1 receptor-independent decrease of transmembrane currents in vivo. Mol Cell Neurosci 22(4):487–500PubMedGoogle Scholar
  27. 27.
    Dinarello CA, Simon A, van der Meer JW (2012) Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 11(8):633–652PubMedCentralPubMedGoogle Scholar
  28. 28.
    Dube C, Vezzani A, Behrens M, Bartfai T, Baram TZ (2005) Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol 57(1):152–155PubMedCentralPubMedGoogle Scholar
  29. 29.
    Eid T, Thomas MJ, Spencer DD, Runden-Pran E, Lai JC, Malthankar GV et al (2004) Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363(9402):28–37PubMedGoogle Scholar
  30. 30.
    Fabene PF, Navarro Mora G, Martinello M, Rossi B, Merigo F, Ottoboni L et al (2008) A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14(12):1377–1383PubMedCentralPubMedGoogle Scholar
  31. 31.
    Ferrari CC, Depino AM, Prada F, Muraro N, Campbell S, Podhajcer O et al (2004) Reversible demyelination, blood–brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain. Am J Pathol 165(5):1827–1837PubMedCentralPubMedGoogle Scholar
  32. 32.
    Fonseca CG, Green CR, Nicholson LF (2002) Upregulation in astrocytic connexin 43 gap junction levels may exacerbate generalized seizures in mesial temporal lobe epilepsy. Brain Res 929(1):105–116PubMedGoogle Scholar
  33. 33.
    Friedman A, Kaufer D, Heinemann U (2009) Blood–brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy. Epilepsy Res 85(2–3):142–149PubMedCentralPubMedGoogle Scholar
  34. 34.
    Frigerio F, Frasca A, Weissberg I, Parrella S, Friedman A, Vezzani A et al (2012) Long-lasting pro-ictogenic effects induced in vivo by rat brain exposure to serum albumin in the absence of concomitant pathology. Epilepsia 53(11):1887–1897PubMedCentralPubMedGoogle Scholar
  35. 35.
    Furukawa K, Mattson MP (1998) The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J Neurochem 70(5):1876–1886PubMedGoogle Scholar
  36. 36.
    Gibbons MB, Smeal RM, Takahashi DK, Vargas JR, Wilcox KS (2013) Contributions of astrocytes to epileptogenesis following status epilepticus: opportunities for preventive therapy? Neurochem Int 63:660–669PubMedGoogle Scholar
  37. 37.
    Hennessy EJ, Parker AE, O’Neill LA (2010) Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 9(4):293–307PubMedGoogle Scholar
  38. 38.
    Hinterkeuser S, Schroder W, Hager G, Seifert G, Blumcke I, Elger CE et al (2000) Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. Eur J Neurosci 12(6):2087–2096PubMedGoogle Scholar
  39. 39.
    Holtman L, van Vliet EA, Edelbroek PM, Aronica E, Gorter JA (2010) Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy. Epilepsy Res 91(1):49–56PubMedGoogle Scholar
  40. 40.
    Iori V, Maroso M, Rizzi M, Iyer AM, Vertemara R, Carli M et al (2013) Receptor for advanced glycation endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures. Neurobiol Dis 58:102–114PubMedGoogle Scholar
  41. 41.
    Iyer A, Zurolo E, Spliet WG, van Rijen PC, Baayen JC, Gorter JA et al (2010) Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 51(9):1763–1773PubMedGoogle Scholar
  42. 42.
    Jiang J, Dingledine R (2013) Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends Pharmacol Sci 34(7):413–423PubMedGoogle Scholar
  43. 43.
    Jiang J, Quan Y, Ganesh T, Pouliot WA, Dudek FE, Dingledine R (2013) Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc Natl Acad Sci U S A 110(9):3591–3596PubMedCentralPubMedGoogle Scholar
  44. 44.
    Jin X, Gereau RW (2006) Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J Neurosci 26(1):246–255PubMedGoogle Scholar
  45. 45.
    Jung KH, Chu K, Lee ST, Kim J, Sinn DI, Kim JM et al (2006) Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol Dis 23(2):237–246PubMedGoogle Scholar
  46. 46.
    Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28(20):5189–5194PubMedCentralPubMedGoogle Scholar
  47. 47.
    Kirkman NJ, Libbey JE, Wilcox KS, White HS, Fujinami RS (2010) Innate but not adaptive immune responses contribute to behavioral seizures following viral infection. Epilepsia 51(3):454–464Google Scholar
  48. 48.
    Koller H, Allert N, Oel D, Stoll G, Siebler M (1998) TNF alpha induces a protein kinase C-dependent reduction in astroglial K+ conductance. Neuroreport 9(7):1375–1378PubMedGoogle Scholar
  49. 49.
    Kovacs Z, Czurko A, Kekesi KA, Juhasz G (2011) Intracerebroventricularly administered lipopolysaccharide enhances spike-wave discharges in freely moving WAG/Rij rats. Brain Res Bull 85(6):410–416PubMedGoogle Scholar
  50. 50.
    Kulkarni SK, Dhir A (2009) Cyclooxygenase in epilepsy: from perception to application. Drugs Today (Barc) 45(2):135–154Google Scholar
  51. 51.
    Kunz T, Oliw EH (2001) The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur J Neurosci 13(3):569–575PubMedGoogle Scholar
  52. 52.
    Kwon YS, Pineda E, Auvin S, Shin D, Mazarati A, Sankar R (2013) Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain. J Neuroinflammation 10:30PubMedCentralPubMedGoogle Scholar
  53. 53.
    Lai AY, Swayze RD, El-Husseini A, Song C (2006) Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons. J Neuroimmunol 175(1–2):97–106PubMedGoogle Scholar
  54. 54.
    Lalic T, Pettingill P, Vincent A, Capogna M (2011) Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission. Epilepsia 52(1):121–131PubMedGoogle Scholar
  55. 55.
    Leonoudakis D, Braithwaite SP, Beattie MS, Beattie EC (2004) TNFalpha-induced AMPA-receptor trafficking in CNS neurons; relevance to excitotoxicity? Neuron Glia Biol 1(3):263–273PubMedCentralPubMedGoogle Scholar
  56. 56.
    Leonoudakis D, Zhao P, Beattie EC (2008) Rapid tumor necrosis factor alpha-induced exocytosis of glutamate receptor 2-lacking AMPA receptors to extrasynaptic plasma membrane potentiates excitotoxicity. J Neurosci 28(9):2119–2130PubMedGoogle Scholar
  57. 57.
    Libbey JE, Kirkman NJ, Smith MC, Tanaka T, Wilcox KS, White HS et al (2008) Seizures following picornavirus infection. Epilepsia 49(6):1066–1074PubMedGoogle Scholar
  58. 58.
    Librizzi L, Noe F, Vezzani A, de Curtis M, Ravizza T (2012) Seizure-induced brain-borne inflammation sustains seizure recurrence and blood–brain barrier damage. Ann Neurol 72(1):82–90PubMedGoogle Scholar
  59. 59.
    Librizzi L, Regondi MC, Pastori C, Frigerio S, Frassoni C, de Curtis M (2007) Expression of adhesion factors induced by epileptiform activity in the endothelium of the isolated guinea pig brain in vitro. Epilepsia 48(4):743–751PubMedGoogle Scholar
  60. 60.
    Lund IV, Hu Y, Raol YH, Benham RS, Faris R, Russek SJ et al (2008) BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway. Sci Signal 1(41):ra9PubMedCentralPubMedGoogle Scholar
  61. 61.
    Ma L, Cui XL, Wang Y, Li XW, Yang F, Wei D et al (2012) Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats. Brain Res 1469:103–113PubMedGoogle Scholar
  62. 62.
    Mandolesi G, Musella A, Gentile A, Grasselli G, Haji N, Sepman H et al (2013) Interleukin-1beta alters glutamate transmission at purkinje cell synapses in a mouse model of multiple sclerosis. J Neurosci 33(29):12105–12121PubMedGoogle Scholar
  63. 63.
    Manto M, Dalmau J, Didelot A, Rogemond V, Honnorat J (2010) In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction. Orphanet J Rare Dis 5:31PubMedCentralPubMedGoogle Scholar
  64. 64.
    Marchi N, Fan Q, Ghosh C, Fazio V, Bertolini F, Betto G et al (2009) Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol Dis 33(2):171–181PubMedCentralPubMedGoogle Scholar
  65. 65.
    Marchi N, Teng Q, Ghosh C, Fan Q, Nguyen MT, Desai NK et al (2010) Blood–brain barrier damage, but not parenchymal white blood cells, is a hallmark of seizure activity. Brain Res 1353:176–186PubMedCentralPubMedGoogle Scholar
  66. 66.
    Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J et al (2011) Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 8(2):304–315PubMedCentralPubMedGoogle Scholar
  67. 67.
    Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM et al (2010) Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 16(4):413–419PubMedGoogle Scholar
  68. 68.
    Mathern GW, Mendoza D, Lozada A, Pretorius JK, Dehnes Y, Danbolt NC et al (1999) Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52(3):453–472PubMedGoogle Scholar
  69. 69.
    Morin-Brureau M, Lebrun A, Rousset MC, Fagni L, Bockaert J, de Bock F et al (2011) Epileptiform activity induces vascular remodeling and zonula occludens 1 downregulation in organotypic hippocampal cultures: role of VEGF signaling pathways. J Neurosci 31(29):10677–10688PubMedGoogle Scholar
  70. 70.
    Naus CC, Bechberger JF, Caveney S, Wilson JX (1991) Expression of gap junction genes in astrocytes and C6 glioma cells. Neurosci Lett 126(1):33–36PubMedGoogle Scholar
  71. 71.
    Nehlig A (2007) What is animal experimentation telling us about new drug treatments of status epilepticus? Epilepsia 48(Suppl 8):78–81PubMedGoogle Scholar
  72. 72.
    Nicolas CS, Peineau S, Amici M, Csaba Z, Fafouri A, Javalet C et al (2012) The Jak/STAT pathway is involved in synaptic plasticity. Neuron 73(2):374–390PubMedCentralPubMedGoogle Scholar
  73. 73.
    Nicoletti JN, Shah SK, McCloskey DP, Goodman JH, Elkady A, Atassi H et al (2008) Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus. Neuroscience 151(1):232–241PubMedCentralPubMedGoogle Scholar
  74. 74.
    Noe FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S et al (2013) Pharmacological blockade of IL-1beta/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis 59:183–193PubMedGoogle Scholar
  75. 75.
    O’Donnell E, Vereker E, Lynch MA (2000) Age-related impairment in LTP is accompanied by enhanced activity of stress-activated protein kinases: analysis of underlying mechanisms. Eur J Neurosci 12(1):345–352PubMedGoogle Scholar
  76. 76.
    Oberheim NA, Tian GF, Han X, Peng W, Takano T, Ransom B et al (2008) Loss of astrocytic domain organization in the epileptic brain. J Neurosci 28(13):3264–3276PubMedGoogle Scholar
  77. 77.
    Oby E, Janigro D (2006) The blood–brain barrier and epilepsy. Epilepsia 47(11):1761–1774PubMedGoogle Scholar
  78. 78.
    Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ et al (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13(5):584–591PubMedCentralPubMedGoogle Scholar
  79. 79.
    Pardo CA, Vining EP, Guo L, Skolasky RL, Carson BS, Freeman JM (2004) The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 45(5):516–526PubMedGoogle Scholar
  80. 80.
    Pedrazzi M, Averna M, Sparatore B, Patrone M, Salamino F, Marcoli M et al (2012) Potentiation of NMDA receptor-dependent cell responses by extracellular high mobility group box 1 protein. PLoS One 7(8):e44518PubMedCentralPubMedGoogle Scholar
  81. 81.
    Pedrazzi M, Raiteri L, Bonanno G, Patrone M, Ledda S, Passalacqua M et al (2006) Stimulation of excitatory amino acid release from adult mouse brain glia subcellular particles by high mobility group box 1 protein. J Neurochem 99(3):827–838PubMedGoogle Scholar
  82. 82.
    Pernhorst K, Herms S, Hoffmann P, Cichon S, Schulz H, Sander T et al (2013) TLR4, ATF-3 and IL8 inflammation mediator expression correlates with seizure frequency in human epileptic brain tissue. Seizure 22(8):675–678PubMedGoogle Scholar
  83. 83.
    Plata-Salaman CR, Ffrench-Mullen JM (1992) Interleukin-1 beta depresses calcium currents in CA1 hippocampal neurons at pathophysiological concentrations. Brain Res Bull 29(2):221–223PubMedGoogle Scholar
  84. 84.
    Plata-Salaman CR, ffrench-Mullen JM (1994) Interleukin-1 beta inhibits Ca2+ channel currents in hippocampal neurons through protein kinase C. Eur J Pharmacol 266(1):1–10PubMedGoogle Scholar
  85. 85.
    Polascheck N, Bankstahl M, Loscher W (2010) The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol 224(1):219–233PubMedGoogle Scholar
  86. 86.
    Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MG, Schrama LH et al (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125(Pt 1):32–43PubMedGoogle Scholar
  87. 87.
    Ravizza T, Lucas SM, Balosso S, Bernardino L, Ku G, Noe F et al (2006) Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47(7):1160–1168PubMedGoogle Scholar
  88. 88.
    Ravizza T, Noe F, Zardoni D, Vaghi V, Sifringer M, Vezzani A (2008) Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol Dis 31(3):327–333PubMedGoogle Scholar
  89. 89.
    Riazi K, Galic MA, Pittman QJ (2010) Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res 89(1):34–42PubMedGoogle Scholar
  90. 90.
    Rodgers KM, Hutchinson MR, Northcutt A, Maier SF, Watkins LR, Barth DS (2009) The cortical innate immune response increases local neuronal excitability leading to seizures. Brain 132(Pt 9):2478–2486PubMedCentralPubMedGoogle Scholar
  91. 91.
    Sanchez-Alavez M, Tabarean IV, Behrens MM, Bartfai T (2006) Ceramide mediates the rapid phase of febrile response to IL-1beta. Proc Natl Acad Sci U S A 103(8):2904–2908PubMedCentralPubMedGoogle Scholar
  92. 92.
    Santello M, Bezzi P, Volterra A (2011) TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69(5):988–1001PubMedGoogle Scholar
  93. 93.
    Santello M, Volterra A (2012) TNFalpha in synaptic function: switching gears. Trends Neurosci 35(10):638–647PubMedGoogle Scholar
  94. 94.
    Sarac S, Afzal S, Broholm H, Madsen FF, Ploug T, Laursen H (2009) Excitatory amino acid transporters EAAT-1 and EAAT-2 in temporal lobe and hippocampus in intractable temporal lobe epilepsy. APMIS 117(4):291–301PubMedGoogle Scholar
  95. 95.
    Schafers M, Sorkin L (2008) Effect of cytokines on neuronal excitability. Neurosci Lett 437(3):188–193PubMedGoogle Scholar
  96. 96.
    Schneider H, Pitossi F, Balschun D, Wagner A, del Rey A, Besedovsky HO (1998) A neuromodulatory role of interleukin-1beta in the hippocampus. Proc Natl Acad Sci U S A 95(13):7778–7783PubMedCentralPubMedGoogle Scholar
  97. 97.
    Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U et al (2004) Lasting blood–brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 24(36):7829–7836PubMedGoogle Scholar
  98. 98.
    Smeal RM, Stewart KA, Iacob E, Fujinami RS, White HS, Wilcox KS (2012) The activity within the CA3 excitatory network during Theiler’s virus encephalitis is distinct from that observed during chronic epilepsy. J Neurovirol 18(1):30–44PubMedGoogle Scholar
  99. 99.
    Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32(12):638–647PubMedCentralPubMedGoogle Scholar
  100. 100.
    Sotgiu S, Murrighile MR, Constantin G (2010) Treatment of refractory epilepsy with natalizumab in a patient with multiple sclerosis. Case report. BMC Neurol 10:84PubMedCentralPubMedGoogle Scholar
  101. 101.
    Steinmetz CC, Turrigiano GG (2010) Tumor necrosis factor-alpha signaling maintains the ability of cortical synapses to express synaptic scaling. J Neurosci 30(44):14685–14690PubMedCentralPubMedGoogle Scholar
  102. 102.
    Stellwagen D, Beattie EC, Seo JY, Malenka RC (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 25(12):3219–3228PubMedGoogle Scholar
  103. 103.
    Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440(7087):1054–1059PubMedGoogle Scholar
  104. 104.
    Stewart KA, Wilcox KS, Fujinami RS, White HS (2010) Development of postinfection epilepsy after Theiler’s virus infection of C57BL/6 mice. J Neuropathol Exp Neurol 69(12):1210–1219PubMedCentralPubMedGoogle Scholar
  105. 105.
    Tabarean IV, Korn H, Bartfai T (2006) Interleukin-1beta induces hyperpolarization and modulates synaptic inhibition in preoptic and anterior hypothalamic neurons. Neuroscience 141(4):1685–1695PubMedGoogle Scholar
  106. 106.
    Takahashi DK, Vargas JR, Wilcox KS (2010) Increased coupling and altered glutamate transport currents in astrocytes following kainic-acid-induced status epilepticus. Neurobiol Dis 40(3):573–585PubMedCentralPubMedGoogle Scholar
  107. 107.
    Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R et al (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281(30):21362–21368PubMedGoogle Scholar
  108. 108.
    Theodore WH, Epstein L, Gaillard WD, Shinnar S, Wainwright MS, Jacobson S (2008) Human herpes virus 6B: a possible role in epilepsy? Epilepsia 49(11):1828–1837PubMedCentralPubMedGoogle Scholar
  109. 109.
    Uva L, Librizzi L, Marchi N, Noe F, Bongiovanni R, Vezzani A et al (2008) Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood–brain barrier permeability. Neuroscience 151(1):303–312PubMedCentralPubMedGoogle Scholar
  110. 110.
    van Gassen KL, de Wit M, Koerkamp MJ, Rensen MG, van Rijen PC, Holstege FC et al (2008) Possible role of the innate immunity in temporal lobe epilepsy. Epilepsia 49(6):1055–1065PubMedGoogle Scholar
  111. 111.
    van Vliet EA, Zibell G, Pekcec A, Schlichtiger J, Edelbroek PM, Holtman L et al (2010) COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats. Neuropharmacology 58(2):404–412PubMedGoogle Scholar
  112. 112.
    Vargas JR, Takahashi DK, Thomson KE, Wilcox KS (2013) The expression of kainate receptor subunits in hippocampal astrocytes after experimentally induced status epilepticus. J Neuropathol Exp Neurol 72(10):919–932PubMedGoogle Scholar
  113. 113.
    Vezzani A, Balosso S, Maroso M, Zardoni D, Noe F, Ravizza T (2010) ICE/caspase 1 inhibitors and IL-1beta receptor antagonists as potential therapeutics in epilepsy. Curr Opin Investig Drugs 11(1):43–50PubMedGoogle Scholar
  114. 114.
    Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F et al (1999) Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci 19(12):5054–5065PubMedGoogle Scholar
  115. 115.
    Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7(1):31–40PubMedCentralPubMedGoogle Scholar
  116. 116.
    Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24PubMedCentralPubMedGoogle Scholar
  117. 117.
    Vezzani A, Janigro D (2009) Leukocyte-endothelial adhesion mechanisms in epilepsy: cheers and jeers. Epilepsy Curr 9(4):118–121PubMedCentralPubMedGoogle Scholar
  118. 118.
    Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T (2011) IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun 25(7):1281–1289PubMedGoogle Scholar
  119. 119.
    Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A et al (2000) Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A 97(21):11534–11539PubMedCentralPubMedGoogle Scholar
  120. 120.
    Vincent A, Irani SR, Lang B (2011) Potentially pathogenic autoantibodies associated with epilepsy and encephalitis in children and adults. Epilepsia 52(Suppl 8):8–11PubMedGoogle Scholar
  121. 121.
    Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T et al (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23(25):8692–8700PubMedGoogle Scholar
  122. 122.
    Viviani B, Gardoni F, Marinovich M (2007) Cytokines and neuronal ion channels in health and disease. Int Rev Neurobiol 82:247–263PubMedGoogle Scholar
  123. 123.
    Wang S, Cheng Q, Malik S, Yang J (2000) Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. J Pharmacol Exp Ther 292(2):497–504PubMedGoogle Scholar
  124. 124.
    Weinberg MS, Blake BL, McCown TJ (2013) Opposing actions of hippocampus TNFalpha receptors on limbic seizure susceptibility. Exp Neurol 247:429–437PubMedGoogle Scholar
  125. 125.
    Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M et al (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci U S A 103(46):17513–17518PubMedCentralPubMedGoogle Scholar
  126. 126.
    Yin HZ, Hsu CI, Yu S, Rao SD, Sorkin LS, Weiss JH (2012) TNF-alpha triggers rapid membrane insertion of Ca(2+) permeable AMPA receptors into adult motor neurons and enhances their susceptibility to slow excitotoxic injury. Exp Neurol 238(2):93–102PubMedCentralPubMedGoogle Scholar
  127. 127.
    Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25(2):181–213PubMedGoogle Scholar
  128. 128.
    Zattoni M, Mura ML, Deprez F, Schwendener RA, Engelhardt B, Frei K et al (2011) Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J Neurosci 31(11):4037–4050PubMedGoogle Scholar
  129. 129.
    Zeise ML, Espinoza J, Morales P, Nalli A (1997) Interleukin-1beta does not increase synaptic inhibition in hippocampal CA3 pyramidal and dentate gyrus granule cells of the rat in vitro. Brain Res 768(1–2):341–344PubMedGoogle Scholar
  130. 130.
    Zhang J, Takahashi HK, Liu K, Wake H, Liu R, Maruo T et al (2011) Anti-high mobility group box-1 monoclonal antibody protects the blood–brain barrier from ischemia-induced disruption in rats. Stroke 42(5):1420–1428PubMedGoogle Scholar
  131. 131.
    Zhang R, Sun L, Hayashi Y, Liu X, Koyama S, Wu Z et al (2010) Acute p38-mediated inhibition of NMDA-induced outward currents in hippocampal CA1 neurons by interleukin-1beta. Neurobiol Dis 38(1):68–77PubMedGoogle Scholar
  132. 132.
    Zhou C, Tai C, Ye HH, Ren X, Chen JG, Wang SQ et al (2006a) Interleukin-1beta downregulates the L-type Ca2+ channel activity by depressing the expression of channel protein in cortical neurons. J Cell Physiol 206(3):799–806Google Scholar
  133. 133.
    Zhou C, Ye HH, Wang SQ, Chai Z (2006b) Interleukin-1beta regulation of N-type Ca2+ channels in cortical neurons. Neurosci Lett 403(1–2):181–185Google Scholar
  134. 134.
    Zurolo E, de Groot M, Iyer A, Anink J, van Vliet EA, Heimans JJ et al (2012) Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 beta. J Neuroinflammation 9:280PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyUniversity of UtahSalt Lake CityUSA
  2. 2.Department of NeuroscienceIRCSS-Istituto di Ricerche Farmacologiche “Mario Negri”MilanItaly

Personalised recommendations