Skip to main content
SpringerLink
Log in

Does Brain Inflammation Mediate Pathological Outcomes in Epilepsy?

  • Chapter
  • First Online:
Issues in Clinical Epileptology: A View from the Bench

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 813))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  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):259–269

    CAS  PubMed  Google Scholar 

  2. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22(5):208–215

    CAS  PubMed  Google Scholar 

  3. Aronica E, Ravizza T, Zurolo E, Vezzani A (2012) Astrocyte immune responses in epilepsy. Glia 60(8):1258–1268

    PubMed  Google Scholar 

  4. Aronica E, Sandau US, Iyer A, Boison D (2013) Glial adenosine kinase – a neuropathological marker of the epileptic brain. Neurochem Int 63:688–695

    CAS  PubMed  Google Scholar 

  5. Auvin S, Mazarati A, Shin D, Sankar R (2010) Inflammation enhances epileptogenesis in the developing rat brain. Neurobiol Dis 40(1):303–310

    CAS  PubMed Central  PubMed  Google Scholar 

  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):34–38

    CAS  PubMed Central  PubMed  Google Scholar 

  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):3256–3265

    PubMed Central  PubMed  Google Scholar 

  8. Balosso S, Ravizza T, Aronica E, Vezzani A (2013) The dual role of TNF-alpha and its receptors in seizures. Exp Neurol 247C:267–271

    Google Scholar 

  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):804–812

    CAS  PubMed  Google Scholar 

  10. Bauer J, Vezzani A, Bien CG (2012) Epileptic encephalitis: the role of the innate and adaptive immune system. Brain Pathol 22(3):412–421

    CAS  PubMed  Google Scholar 

  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):2282–2285

    CAS  PubMed  Google Scholar 

  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):227–234

    CAS  PubMed  Google Scholar 

  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):543–550

    CAS  PubMed  Google Scholar 

  14. Bittner S, Simon OJ, Gobel K, Bien CG, Meuth SG, Wiendl H (2013) Rasmussen encephalitis treated with natalizumab. Neurology 81(4):395–397

    PubMed  Google Scholar 

  15. Boison D (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 65(3):906–943

    CAS  PubMed Central  PubMed  Google Scholar 

  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):8927–8935

    CAS  PubMed Central  PubMed  Google Scholar 

  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):487–501

    Google Scholar 

  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):881–892

    CAS  Google Scholar 

  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):77–87

    CAS  PubMed  Google Scholar 

  20. Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60(8):1215–1226

    PubMed Central  PubMed  Google Scholar 

  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):1849–1860

    CAS  PubMed Central  PubMed  Google Scholar 

  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):10588–10599

    CAS  PubMed Central  PubMed  Google Scholar 

  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):1379–1389

    CAS  PubMed  Google Scholar 

  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):2623–2633

    PubMed  Google Scholar 

  25. Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA (2013) Glia and epilepsy: excitability and inflammation. Trends Neurosci 36(3):174–184

    CAS  PubMed  Google Scholar 

  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):487–500

    CAS  PubMed  Google Scholar 

  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):633–652

    CAS  PubMed Central  PubMed  Google Scholar 

  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):152–155

    CAS  PubMed Central  PubMed  Google Scholar 

  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):28–37

    CAS  PubMed  Google Scholar 

  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):1377–1383

    CAS  PubMed Central  PubMed  Google Scholar 

  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):1827–1837

    CAS  PubMed Central  PubMed  Google Scholar 

  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):105–116

    CAS  PubMed  Google Scholar 

  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):142–149

    CAS  PubMed Central  PubMed  Google Scholar 

  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):1887–1897

    CAS  PubMed Central  PubMed  Google Scholar 

  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):1876–1886

    CAS  PubMed  Google Scholar 

  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 63:660–669

    CAS  PubMed  Google Scholar 

  37. Hennessy EJ, Parker AE, O’Neill LA (2010) Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 9(4):293–307

    CAS  PubMed  Google Scholar 

  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):2087–2096

    CAS  PubMed  Google Scholar 

  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):49–56

    CAS  PubMed  Google Scholar 

  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 58:102–114

    CAS  PubMed  Google Scholar 

  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):1763–1773

    CAS  PubMed  Google Scholar 

  42. Jiang J, Dingledine R (2013) Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends Pharmacol Sci 34(7):413–423

    CAS  PubMed  Google Scholar 

  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):3591–3596

    CAS  PubMed Central  PubMed  Google Scholar 

  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):246–255

    CAS  PubMed  Google Scholar 

  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):237–246

    CAS  PubMed  Google Scholar 

  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):5189–5194

    CAS  PubMed Central  PubMed  Google Scholar 

  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):454–464

    Google Scholar 

  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):1375–1378

    CAS  PubMed  Google Scholar 

  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):410–416

    CAS  PubMed  Google Scholar 

  50. Kulkarni SK, Dhir A (2009) Cyclooxygenase in epilepsy: from perception to application. Drugs Today (Barc) 45(2):135–154

    CAS  Google Scholar 

  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):569–575

    CAS  PubMed  Google Scholar 

  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 10:30

    CAS  PubMed Central  PubMed  Google Scholar 

  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):97–106

    CAS  PubMed  Google Scholar 

  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):121–131

    PubMed  Google Scholar 

  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):263–273

    PubMed Central  PubMed  Google Scholar 

  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):2119–2130

    CAS  PubMed  Google Scholar 

  57. Libbey JE, Kirkman NJ, Smith MC, Tanaka T, Wilcox KS, White HS et al (2008) Seizures following picornavirus infection. Epilepsia 49(6):1066–1074

    PubMed  Google Scholar 

  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):82–90

    PubMed  Google Scholar 

  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):743–751

    CAS  PubMed  Google Scholar 

  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):ra9

    PubMed Central  PubMed  Google Scholar 

  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 1469:103–113

    CAS  PubMed  Google Scholar 

  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):12105–12121

    CAS  PubMed  Google Scholar 

  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 5:31

    PubMed Central  PubMed  Google Scholar 

  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):171–181

    CAS  PubMed Central  PubMed  Google Scholar 

  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 1353:176–186

    CAS  PubMed Central  PubMed  Google Scholar 

  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):304–315

    CAS  PubMed Central  PubMed  Google Scholar 

  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):413–419

    CAS  PubMed  Google Scholar 

  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):453–472

    CAS  PubMed  Google Scholar 

  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):10677–10688

    CAS  PubMed  Google Scholar 

  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):33–36

    CAS  PubMed  Google Scholar 

  71. Nehlig A (2007) What is animal experimentation telling us about new drug treatments of status epilepticus? Epilepsia 48(Suppl 8):78–81

    CAS  PubMed  Google Scholar 

  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):374–390

    CAS  PubMed Central  PubMed  Google Scholar 

  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):232–241

    CAS  PubMed Central  PubMed  Google Scholar 

  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 59:183–193

    CAS  PubMed  Google Scholar 

  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):345–352

    PubMed  Google Scholar 

  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):3264–3276

    CAS  PubMed  Google Scholar 

  77. Oby E, Janigro D (2006) The blood–brain barrier and epilepsy. Epilepsia 47(11):1761–1774

    CAS  PubMed  Google Scholar 

  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):584–591

    CAS  PubMed Central  PubMed  Google Scholar 

  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):516–526

    PubMed  Google Scholar 

  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):e44518

    CAS  PubMed Central  PubMed  Google Scholar 

  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):827–838

    CAS  PubMed  Google Scholar 

  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):675–678

    PubMed  Google Scholar 

  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):221–223

    CAS  PubMed  Google Scholar 

  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):1–10

    CAS  PubMed  Google Scholar 

  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):219–233

    CAS  PubMed  Google Scholar 

  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):32–43

    CAS  PubMed  Google Scholar 

  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):1160–1168

    CAS  PubMed  Google Scholar 

  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):327–333

    CAS  PubMed  Google Scholar 

  89. Riazi K, Galic MA, Pittman QJ (2010) Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res 89(1):34–42

    CAS  PubMed  Google Scholar 

  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):2478–2486

    PubMed Central  PubMed  Google Scholar 

  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):2904–2908

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Santello M, Bezzi P, Volterra A (2011) TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69(5):988–1001

    CAS  PubMed  Google Scholar 

  93. Santello M, Volterra A (2012) TNFalpha in synaptic function: switching gears. Trends Neurosci 35(10):638–647

    CAS  PubMed  Google Scholar 

  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):291–301

    CAS  PubMed  Google Scholar 

  95. Schafers M, Sorkin L (2008) Effect of cytokines on neuronal excitability. Neurosci Lett 437(3):188–193

    PubMed  Google Scholar 

  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):7778–7783

    CAS  PubMed Central  PubMed  Google Scholar 

  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):7829–7836

    CAS  PubMed  Google Scholar 

  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):30–44

    PubMed  Google Scholar 

  99. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32(12):638–647

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Sotgiu S, Murrighile MR, Constantin G (2010) Treatment of refractory epilepsy with natalizumab in a patient with multiple sclerosis. Case report. BMC Neurol 10:84

    PubMed Central  PubMed  Google Scholar 

  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):14685–14690

    CAS  PubMed Central  PubMed  Google Scholar 

  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):3219–3228

    CAS  PubMed  Google Scholar 

  103. Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440(7087):1054–1059

    CAS  PubMed  Google Scholar 

  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):1210–1219

    PubMed Central  PubMed  Google Scholar 

  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):1685–1695

    CAS  PubMed  Google Scholar 

  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):573–585

    CAS  PubMed Central  PubMed  Google Scholar 

  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):21362–21368

    CAS  PubMed  Google Scholar 

  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):1828–1837

    PubMed Central  PubMed  Google Scholar 

  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):303–312

    CAS  PubMed Central  PubMed  Google Scholar 

  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):1055–1065

    PubMed  Google Scholar 

  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):404–412

    PubMed  Google Scholar 

  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):919–932

    CAS  PubMed  Google Scholar 

  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):43–50

    CAS  PubMed  Google Scholar 

  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):5054–5065

    CAS  PubMed  Google Scholar 

  115. Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7(1):31–40

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Vezzani A, Janigro D (2009) Leukocyte-endothelial adhesion mechanisms in epilepsy: cheers and jeers. Epilepsy Curr 9(4):118–121

    PubMed Central  PubMed  Google Scholar 

  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):1281–1289

    CAS  PubMed  Google Scholar 

  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):11534–11539

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Vincent A, Irani SR, Lang B (2011) Potentially pathogenic autoantibodies associated with epilepsy and encephalitis in children and adults. Epilepsia 52(Suppl 8):8–11

    CAS  PubMed  Google Scholar 

  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):8692–8700

    CAS  PubMed  Google Scholar 

  122. Viviani B, Gardoni F, Marinovich M (2007) Cytokines and neuronal ion channels in health and disease. Int Rev Neurobiol 82:247–263

    CAS  PubMed  Google Scholar 

  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):497–504

    CAS  PubMed  Google Scholar 

  124. Weinberg MS, Blake BL, McCown TJ (2013) Opposing actions of hippocampus TNFalpha receptors on limbic seizure susceptibility. Exp Neurol 247:429–437

    CAS  PubMed  Google Scholar 

  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):17513–17518

    CAS  PubMed Central  PubMed  Google Scholar 

  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):93–102

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25(2):181–213

    CAS  PubMed  Google Scholar 

  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):4037–4050

    CAS  PubMed  Google Scholar 

  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):341–344

    CAS  PubMed  Google Scholar 

  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):1420–1428

    CAS  PubMed  Google Scholar 

  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):68–77

    PubMed  Google Scholar 

  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):799–806

    CAS  Google Scholar 

  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):181–185

    CAS  Google Scholar 

  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 9:280

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, 84108, USA

    Karen S. Wilcox

  2. Department of Neuroscience, IRCSS-Istituto di Ricerche Farmacologiche “Mario Negri”, via G. La Masa 19, Milan, 20156, Italy

    Annamaria Vezzani

Authors
  1. Karen S. Wilcox
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annamaria Vezzani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karen S. Wilcox .

Editor information

Editors and Affiliations

  1. Dept. of Child & Adoles. Psych., Phys. & Neurosc., and Psych., New York Univ. Langone Med. Ctr., Orangeburg, New York, USA

    Helen E. Scharfman

  2. Dept. of Comp. Med. and Neurol. & Neurol. Scs., Stanford University, Stanford, California, USA

    Paul S. Buckmaster

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Wilcox, K.S., Vezzani, A. (2014). Does Brain Inflammation Mediate Pathological Outcomes in Epilepsy?. In: Scharfman, H., Buckmaster, P. (eds) Issues in Clinical Epileptology: A View from the Bench. Advances in Experimental Medicine and Biology, vol 813. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8914-1_14

Download citation

  • DOI: https://doi.org/10.1007/978-94-017-8914-1_14

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-017-8913-4

  • Online ISBN: 978-94-017-8914-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation