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Issues in Clinical Epileptology: A View from the Bench pp 109–122Cite as

When and How Do Seizures Kill Neurons, and Is Cell Death Relevant to Epileptogenesis?

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

Abstract

The effect of seizures on neuronal death and the role of seizure-induced neuronal death in acquired epileptogenesis have been debated for decades. Isolated brief seizures probably do not kill neurons; however, severe and repetitive seizures (i.e., status epilepticus) certainly do. Because status epilepticus both kills neurons and also leads to chronic epilepsy, neuronal death has been proposed to be an integral part of acquired epileptogenesis. Several studies, particularly in the immature brain, have suggested that neuronal death is not necessary for acquired epileptogenesis; however, the lack of neuronal death is difficult if not impossible to prove, and more recent studies have challenged this concept. Novel mechanisms of cell death, beyond the traditional concepts of necrosis and apoptosis, include autophagy, phagoptosis, necroptosis, and pyroptosis. The traditional proposal for why neuronal death may be necessary for epileptogenesis is based on the recapitulation of development hypothesis, where a loss of synaptic input from the dying neurons is considered a critical signal to induce axonal sprouting and synaptic-circuit reorganization. We propose a second hypothesis – the neuronal death pathway hypothesis, which states that the biochemical pathways causing programmed neurodegeneration, rather than neuronal death per se, are responsible for or contribute to epileptogenesis. The reprogramming of neuronal death pathways – if true – is proposed to derive from necroptosis or pyroptosis. The proposed new hypothesis may inform on why neuronal death seems closely linked to epileptogenesis, but may not always be.

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References

  1. Balosso S, Maroso M, Sanchez-Alavez M, Ravizza T, Frasca A, Bartfai T, Vezzani A (2008) A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain 131:3256–3265

    Article  PubMed Central  PubMed  Google Scholar 

  2. Bergsbaken T, Fink SL, Cookson BT (2009) Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7:99–109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT (2010) Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68:19–31

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5

    Article  CAS  PubMed  Google Scholar 

  5. Billadeau DD, Leibson PJ (2002) ITAMs versus ITIMs: striking a balance during cell regulation. J Clin Invest 109:161–168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Boise LH, Collins CM (2001) Salmonella-induced cell death: apoptosis, necrosis or programmed cell death? Trends Microbiol 9:64–67

    Article  CAS  PubMed  Google Scholar 

  7. Brennan MA, Cookson BT (2000) Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol 38:31–40

    Article  CAS  PubMed  Google Scholar 

  8. Brown GC, Neher JJ (2012) Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’. Trends Biochem Sci 37:325–332

    Article  CAS  PubMed  Google Scholar 

  9. Buckmaster PS (2014) Does mossy fiber sprouting give rise to the epileptic state? In: Issues in clinical epileptology: a view from the bench. Springer, Dordrecht, pp 161–168

    Google Scholar 

  10. Buckmaster PS, Dudek FE (1997) Neuron loss, granule cell axon reorganization, and functional changes in dentate gyrus of epileptic kainate-treated rats. J Comp Neurol 385:385–404

    Article  CAS  PubMed  Google Scholar 

  11. Bursch W (2001) The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ 8:569–581

    Article  CAS  PubMed  Google Scholar 

  12. Busser J, Geldmacher DS, Herrup K (1998) Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci 18:2801–2807

    CAS  PubMed  Google Scholar 

  13. Cardona AE, Huang D, Sasse ME, Ransohoff RM (2006) Isolation of murine microglial cells for RNA analysis or flow cytometry. Nat Protoc 1:1947–1951

    Article  CAS  PubMed  Google Scholar 

  14. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924

    Article  CAS  PubMed  Google Scholar 

  15. Cavalheiro EA, Leite JP, Borolotto ZA, Turski WA, Ikonomidou C, Turski L (1991) Long-term effects of pilocarpine in rats: structural damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia 32:778–782

    Article  CAS  PubMed  Google Scholar 

  16. Cavalheiro EA, Silva DF, Turski WA, Calderazzo-Filho LS, Bortolotto ZA, Turski L (1987) The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Brain Res 465:43–58

    Article  CAS  PubMed  Google Scholar 

  17. Chen Y, Smith MR, Thirumalai K, Zychlinsky A (1996) A bacterial invasin induces macrophage apoptosis by binding directly to ICE. EMBO J 15:3853–3860

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Cookson BT, Brennan MA (2001) Pro-inflammatory programmed cell death. Trends Microbiol 9:113–114

    Article  CAS  PubMed  Google Scholar 

  19. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758

    Article  CAS  PubMed  Google Scholar 

  20. De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, De Luigi A, Garattini S, Vezzani A (2000) Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci 12:2623–2633

    Article  PubMed  Google Scholar 

  21. Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, Muller M, Kreymborg K, Altenberend F, Brandenburg J, Kalbacher H, Brock R, Driessen C, Rammensee HG, Stevanovic S (2005) Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A 102:7922–7927

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Dudek FE, Staley KJ (2011) The time course of acquired epilepsy. Implications for therapeutic intervention to suppress epileptogenesis. Neurosci Lett 497:240–246

    Article  CAS  PubMed  Google Scholar 

  23. Dudek FE, Sutula TP (2007) Chapter 41: Epileptogenesis in the dentate gyrus: a critical perspective. In: Scharfman HE (ed) Progress in brain research, vol 163. Elsevier B.V., Amsterdam, pp 755–773

    Google Scholar 

  24. Ekstrand JJ, Pouliot W, Scheerlinck P, Dudek FE (2011) Lithium pilocarpine-induced status epilepticus in postnatal day 20 rats results in greater neuronal injury in ventral versus dorsal hippocampus. Neuroscience 192:699–707

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Hacker G, Leverkus M (2011) cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell 43:449–463

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Fink SL, Cookson BT (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 73:1907–1916

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Frantz S, Ducharme A, Sawyer D, Rohde LE, Kobzik L, Fukazawa R, Tracey D, Allen H, Lee RT, Kelly RA (2003) Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. J Mol Cell Cardiol 35:685–694

    Article  CAS  PubMed  Google Scholar 

  28. Fricker M, Neher JJ, Zhao JW, Thery C, Tolkovsky AM, Brown GC (2012) MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation. J Neurosci 32:2657–2666

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Fujikawa DG (1996) The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res 725:11–22

    Article  CAS  PubMed  Google Scholar 

  30. Galanopoulou AS, Moshe SL (2014) Does epilepsy cause a reversion to immature function? In: Issues in clinical epileptology: a view from the bench. Springer, Dordrecht

    Google Scholar 

  31. Galic MA, Riazi K, Pittman QJ (2012) Cytokines and brain excitability. Front Neuroendocrinol 33:116–125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–334

    Article  CAS  PubMed  Google Scholar 

  33. Gowers WR (1881) Epilepsy and other chronic convulsive diseases: their causes, symptoms and treatment. J & A Churchill, London

    Google Scholar 

  34. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:387–1394

    Article  Google Scholar 

  35. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889

    Article  CAS  PubMed  Google Scholar 

  36. Haut SR (2006) Seizure clustering. Epilepsy Behav 8:50–55

    Article  PubMed  Google Scholar 

  37. Haut SR, Shinnar S, Moshé SL, O’Dell C, Legatt AD (1999) The association between seizure clustering and convulsive status epilepticus in patients with intractable complex partial seizures. Epilepsia 40:1832–1834

    Article  CAS  PubMed  Google Scholar 

  38. Haut SR, Velíšková J, Moshé SL (2004) Susceptibility of immature and adult brains to seizure effects. Lancet Neurol 3:608–617

    Article  PubMed  Google Scholar 

  39. Herrup K, Yang Y (2007) Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci 8:368–378

    Article  CAS  PubMed  Google Scholar 

  40. Hirsch E, Baram TZ, Sneed OC III (1992) Otogenic study of lithiumpilocarpine-induced status epilepticus in rats. Brain Res 583:120–126

    Article  CAS  PubMed  Google Scholar 

  41. Hock BJ Jr, Lamb BT (2001) Transgenic mouse models of Alzheimer’s disease. Trends Genet 17:S7–S12

    Article  CAS  PubMed  Google Scholar 

  42. Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, Barclay AN, Sedgwick JD (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768–1771

    Article  CAS  PubMed  Google Scholar 

  43. Hoesche C, Sauerwald A, Veh RW, Krippl B, Kilimann MW (1993) The 5′-flanking region of the rat synapsin I gene directs neuron-specific and developmentally regulated reporter gene expression in transgenic mice. J Biol Chem 268:26494–26502

    CAS  PubMed  Google Scholar 

  44. Jiang J et al (2013) Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc Natl Acad Sci U S A 110:3591–3596

    Google Scholar 

  45. Kaczmarek A, Vandenabeele P, Krysko DV (2013) Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38:209–223

    Article  CAS  PubMed  Google Scholar 

  46. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471:368–372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884

    Article  CAS  PubMed  Google Scholar 

  49. Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, Williams LT (1997) Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science 278:294–298

    Article  CAS  PubMed  Google Scholar 

  50. Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6:513–519

    Article  CAS  PubMed  Google Scholar 

  51. Kubova H, Mares P, Suchomelova L, Brozek G, Druga R, Pitkanen A (2004) Status epilepticus in immature rats leads to behavioural and cognitive impairment and epileptogenesis. Eur J Neurosci 19:3255–3265

    Article  PubMed  Google Scholar 

  52. 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 28:2119–2130

    Article  CAS  PubMed  Google Scholar 

  53. Liu XH, Kwon D, Schielke GP, Yang GY, Silverstein FS, Barks JD (1999) Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage. J Cereb Blood Flow Metab 19:1099–1108

    Article  CAS  PubMed  Google Scholar 

  54. Ma Y, Galluzzi L, Zitvogel L, Kroemer G (2013) Autophagy and cellular immune responses. Immunity 39:211–227

    Article  CAS  PubMed  Google Scholar 

  55. Marcheselli VL, Bazan NG (1996) Sustained induction of prostaglandin endoperoxide synthase-2 by seizures in hippocampus. Inhibition by a platelet-activating factor antagonist. J Biol Chem 271:24794–24799

    Article  CAS  PubMed  Google Scholar 

  56. McGowan E, Eriksen J, Hutton M (2006) A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet 22:281–289

    Article  CAS  PubMed  Google Scholar 

  57. Mello LE, Cavalheiro EA, Tan AM, Kupfer WR, Pretorius JK, Babb TL, Finch DM (1993) Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia 34:985–995

    Article  CAS  PubMed  Google Scholar 

  58. Nagy Z, Esiri M, Cato A, Smith A (1997) Cell cycle markers in the hippocampus in Alzheimer’s disease. Acta Neuropathol (Berl) 94:6–15

    Article  CAS  Google Scholar 

  59. Nairismagi J, Pitkanen A, Kettunen MI, Kauppinen RA, Kubova H (2006) Status epilepticus in 12-day-old rats leads to temporal lobe neurodegeneration and volume reduction: a histologic and MRI study. Epilepsia 47:479–488

    Article  PubMed  Google Scholar 

  60. Neher JJ et al (2013) Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc Natl Acad Sci U S A 110:E4098–4107

    Google Scholar 

  61. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    Article  CAS  PubMed  Google Scholar 

  62. Obenaus A, Esclapez M, Houser CR (1993) Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures. J Neurosci 13:4470–4485

    CAS  PubMed  Google Scholar 

  63. Ogoshi F, Yin HZ, Kuppumbatti Y, Song B, Amindari S, Weiss JH (2005) Tumor necrosis-factor-alpha (TNF-α) induces rapid insertion of Ca2+−permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons. Exp Neurol 193:384–393

    Article  CAS  PubMed  Google Scholar 

  64. Perez-Garijo A, Martin FA, Morata G (2004) Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in drosophila. Development 131:5591–5598

    Article  CAS  PubMed  Google Scholar 

  65. Perry VH, Teeling J (2013) Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 35:601–612

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Plata-Salaman CR, ffrench-Mullen JM (1994) Interleukin-1 beta inhibits Ca2+ channel currents in hippocampal neurons through protein kinase C. Eur J Pharmacol 266:1–10

    Article  CAS  PubMed  Google Scholar 

  67. Pollard H, Charriaut-Marlangue C, Cantagrel S, Represa A, Robain O, Moreau J, Ben-Ari Y (1994) Kainate-induced apoptotic cell death in hippocampal neurons. Neuroscience 63:7–18

    Article  CAS  PubMed  Google Scholar 

  68. Priel MR, dos Santos NF, Cavalheiro EA (1996) Developmental aspects of the pilocarpine model of epilepsy. Epilepsy Res 26:115–121

    Article  CAS  PubMed  Google Scholar 

  69. Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468:253–262

    Article  CAS  PubMed  Google Scholar 

  70. Ravichandran KS (2011) Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35:445–455

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Ravizza T, Lucas SM, Balosso S, Bernardino L, Ku G, Noe F, Malva J, Randle JC, Allan S, Vezzani A (2006) Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47:1160–1168

    Article  CAS  PubMed  Google Scholar 

  72. Rempe D, Vangeison G, Hamilton J, Li Y, Jepson M, Federoff HJ (2006) Synapsin I Cre transgene expression in male mice produces germline recombination in progeny. Genesis 44:44–49

    Article  CAS  PubMed  Google Scholar 

  73. Sandhya TL, Ong WY, Horrocks LA, Farooqui AA (1998) A light and electron microscopic study of cytoplasmic phospholipase A2 and cyclooxygenase-2 in the hippocampus after kainate lesions. Brain Res 788:223–231

    Article  CAS  PubMed  Google Scholar 

  74. Sankar R, Shin DH, Liu H, Mazarati A, Vasconcelos A, Wasterlain CG (1998) Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J Neurosci 18:8382–8393

    CAS  PubMed  Google Scholar 

  75. Sankar R, Shin DH, Wasterlain CG (1997) Serum neuron-specific enolase is a marker for neuronal damage following status epilepticus in the rat. Epilepsy Res 28:129–136

    Article  CAS  PubMed  Google Scholar 

  76. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195

    Article  CAS  PubMed  Google Scholar 

  77. Scholl EA, Dudek FE, Ekstrand JJ (2013) Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat. Neuroscience 12:45–59

    Article  Google Scholar 

  78. Serrano GE, Lelutiu N, Rojas A, Cochi S, Shaw R, Makinson CD, Wang D, FitzGerald GA, Dingledine R (2011) Ablation of cyclooxygenase-2 in forebrain neurons is neuroprotective and dampens brain inflammation after status epilepticus. J Neurosci 31:14850–14860

    Article  CAS  PubMed  Google Scholar 

  79. Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521

    Article  CAS  PubMed  Google Scholar 

  80. Sperber EF, Haas KZ, Stanton PK, Moshe SL (1991) Resistance of the immature hippocampus to seizure-induced synaptic reorganization. Brain Res Dev Brain Res 60:88–93

    Article  CAS  PubMed  Google Scholar 

  81. Stafstrom CE, Thompson JL, Holmes GL (1992) Kainic acid seizures in the developing brain: status epilepticus and spontaneous recurrent seizures. Brain Res Dev Brain Res 65:227–236

    Article  CAS  PubMed  Google Scholar 

  82. 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 25:3219–3228

    Article  CAS  PubMed  Google Scholar 

  83. Sutula TP, Dudek FE (2007) Chapter 29: Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system. In: Scharfman HE (ed) Progress in brain research, vol 163. Elsevier B.V., Amsterdam, pp 541–563

    Google Scholar 

  84. Sutula T, Pitkanen A (2002) Do seizures damage the brain? Elsevier Science, Amsterdam

    Google Scholar 

  85. Turski WA, Cavalheiro EA, Schwarz M, Czuczwar SJ, Kleinrok Z, Turski L (1983) Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study. Behav Brain Res 9:315–335

    Article  CAS  PubMed  Google Scholar 

  86. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714

    Article  CAS  PubMed  Google Scholar 

  87. Van Loo G, Demol H, van Gurp M, Hoorelbeke B, Schotte P, Beyaert R, Zhivotovsky B, Gevaert K, Declercq W, Vandekerckhove J, Vandenabeele P (2002) A matrix-assisted laser desorption ionization post-source decay (MALDI-PSD) analysis of proteins released from isolated liver mitochondria treated with recombinant truncated Bid. Cell Death Differ 9:301–308

    Article  PubMed  Google Scholar 

  88. Varvel NH, Bhaskar K, Patil AR, Pimplikar SW, Herrup K, Lamb BT (2008) Abeta oligomers induce neuronal cell cycle events in Alzheimer’s disease. J Neurosci 28:10786–10793

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Vezzani A, Granata T (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46:1724–1743

    Article  CAS  PubMed  Google Scholar 

  91. Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, De Simoni MG, Sperk G, Andell-Jonsson S, Lundkvist J, Iverfeldt K, Bartfai T (2000) Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A 97:11534–11539

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Vincent I, Jicha G, Rosado M, Dickson D (1997) Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci 17:3588–3598

    CAS  PubMed  Google Scholar 

  93. Vincent I, Rosado M, Davies P (1996) Mitotic mechanisms in Alzheimer’s disease? J Cell Biol 132:413–425

    Article  CAS  PubMed  Google Scholar 

  94. Wang L, Liu Y–H, Huang Y-G, Chen L-W (2008) Time-course of neuronal death in the mouse pilocarpine model of chronic epilepsy using Fluoro-Jade C staining. Brain Res 1241:157–167

    Article  CAS  PubMed  Google Scholar 

  95. 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 292:497–504

    CAS  PubMed  Google Scholar 

  96. Williams PA, Wuarin JP, Dou P, Ferraro DJ, Dudek FE (2002) Reassessment of the effects of cycloheximide on mossy fiber sprouting and epileptogenesis in the pilocarpine model of temporal lobe epilepsy. J Neurophysiol 88:2075–2087

    PubMed  Google Scholar 

  97. Xu Y, Zeng K, Han Y, Wang L, Chen D, Xi Z, Wang H, Wang X, Chen G (2012) Altered expression of CX3CL1 in patients with epilepsy and in a rat model. Am J Pathol 180:1950–1962

    Article  CAS  PubMed  Google Scholar 

  98. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11:371–386

    Article  CAS  PubMed  Google Scholar 

  99. Yang Y, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci 21:2661–2668

    CAS  PubMed  Google Scholar 

  100. Yang Y, Herrup K (2005) Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J Neurosci 25:2522–2529

    Article  CAS  PubMed  Google Scholar 

  101. Yang Y, Varvel NH, Lamb BT, Herrup K (2006) Ectopic cell cycle events link human Alzheimer’s disease and amyloid precursor protein transgenic mouse models. J Neurosci 26:775–784

    Article  CAS  PubMed  Google Scholar 

  102. Zhang S, Wang XJ, Tian LP, Pan J, Lu GQ, Zhang YJ, Ding JQ, Chen SD (2011) CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson’s disease. J Neuroinflammation 8:154

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Zhang WH, Wang X, Narayanan M, Zhang Y, Huo C, Reed JC, Friedlander RM (2003) Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Proc Natl Acad Sci U S A 100:16012–16017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Ray Dingledine first met Phil Schwartzkroin in 1975 just after Phil had returned to Stanford from his postdoctoral stint with Per Andersen in Oslo, little realizing that he would follow in Phil’s footsteps by joining Per’s lab just 2 years later. Ray was in the act of returning some equipment that he had “borrowed” from David Prince’s lab to complete his graduate work, recognizing that it would never be missed in the vast warehouse of the Prince lab. Phil was then, as he is now, a very gracious yet intense scientist, and Ray values his friendship.

Ed Dudek also met Phil in about 1975; we have never worked together, but we have had numerous critical if not intense discussions on a variety of topics. Ed deeply appreciates and respects his thoughtful and constructive criticisms and his kind encouragement; Phil’s traits and his actions have made all of us better scientists and professional colleagues.

Other Acknowledgements

This work is supported by National Institutes of Health awards NS076775, NS074169, and P20 NS080185 (RD) and NS058158 (RD), and NS079135, NS079274, and NS086364 (FED). We thank Jonas Neher (Tuebingen, Germany) and Jeff Ekstrand (Salt Lake City, Utah) for helpful comments as well as Vicki Skelton (Salt Lake City, Utah) for figure preparation and assistance with the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Ray Dingledine & Nicholas H. Varvel

  2. Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA

    F. Edward Dudek

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  1. Ray Dingledine
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Correspondence to Ray Dingledine .

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  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

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Dingledine, R., Varvel, N.H., Dudek, F.E. (2014). When and How Do Seizures Kill Neurons, and Is Cell Death Relevant to Epileptogenesis?. 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_9

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  • DOI: https://doi.org/10.1007/978-94-017-8914-1_9

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