Epilepsy and Cell Death

  • Cheolsu Shin
  • Ki-Hyeong Lee


Epilepsy is one of the most common neurological disorders afflicting mankind. It is a syndrome of unpredictable spontaneous recurrence of seizures. Its prevalence ranges from 1.5 to 19.5 per 1000 depending on the geographical area and the ethnic group (1). Despite all the misconceptions and prejudicial history since the first description of this malady in Hippocrates’ “On the Sacred Disease” 2500 yr ago, there have been dramatic improvements in diagnosis and treatment thanks to the modern brain imaging technology such as magnetic resonance image (MRI), positron emission tomography (PET), and single photon emission tomography (SPECT) as well as various surgical approaches to medically intractable epilepsies. Compared with these marked improvements in diagnostic and treatment modalities, the understanding of the basic patho-physiologic mechanisms of epilepsy remains rather elusive


Status Epilepticus Dentate Gyrus Temporal Lobe Epilepsy Mossy Fiber Perforant Path 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes, and Consequences, Demos Publications, 1990Google Scholar
  2. 2.
    Cotman CW, Monaghan DT, Ottersen J, Storm-Mathisen J. Anatomical organization of excitatory amino acid receptors and their pathways. Trends Neurosci 1987, 10: 273–280.CrossRefGoogle Scholar
  3. 3.
    Bouchet C, Cazauvieilh JB. De Pépilepsie considérée dans ses rapports avec l’aliénation mentale. Archives generales de Medicine (Paris); 1825, 9: 510–542.Google Scholar
  4. 4.
    Margerison JH, Corsellis JAN. Epilepsy and the temporal lobes. A clinical, electro-encephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain; 1966, 89: 499–530.PubMedCrossRefGoogle Scholar
  5. 5.
    Spielmeyer W. Die Pathogenese des epileptischen Krampfes.Zeitschrift fur die gesamte Neurologie und Psychiatrie 1927,; 109: 501–520.CrossRefGoogle Scholar
  6. 6.
    Penfield W, Flanigin H. Surgical therapy of temporal lobe seizures. Arch Neurol Psych 1950, 64: 491–500.CrossRefGoogle Scholar
  7. 7.
    Berg AT, Shinnar S. Unprovoked seizures in children with febrile seizures: Short term outcome. Neurology 1996, 47: 562–568.PubMedCrossRefGoogle Scholar
  8. 8.
    Bruton CJ. The Neuropathology of Temporal Lobe Epilepsy, Oxford Press, NY, 1988.Google Scholar
  9. 9.
    Meldrum BD, Vigoroux RS, Brierly JB. Systemic factors and epileptic brain damage. Arch Neurol 1973, 29: 82–87.PubMedCrossRefGoogle Scholar
  10. 10.
    Sagar HJ, Oxbury JM. Hippocampal neuron loss in temporal lobe epilepsy: correlation with early childhood convulsions. Ann Neurol 1987, 22: 334–340.PubMedCrossRefGoogle Scholar
  11. 11.
    Aicardi J, Chevrie JJ. Consequences of status epilepticus in infants and children, in Status epilepticus: Mechanisms of brain damage and treatment; (Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds.), Raven Press, NY, 1983, pp. 115–125.Google Scholar
  12. 12.
    Corsellis JAN, Brouton CJ. Neuropathology of status epilepticus in humans, in Status epilepticus: Mechanisms of brain damage and treatment; (Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ, eds.), Raven Press, NY, 1983, pp. 129–139.Google Scholar
  13. 13.
    Degiorgio CM, Tomiyasu U, Gott PS, Treiman DM. Hippocampal pyramidal cell loss in human status epilepticus. Epilepsia 1992, 33: 23–27.PubMedCrossRefGoogle Scholar
  14. 14.
    De Lanerolle NC, Kim JH, Robbins RJ, Spencer DD. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res 1989, 495: 387–395.PubMedCrossRefGoogle Scholar
  15. 15.
    Babb TL, Pretorius JK, Kupfer WR, Crandall PH. Glutamate decarboxylase-immunoreac tive neurons are preserved in human epileptic hippocampus. J Neurosci 1989, 9: 2562–2574.PubMedGoogle Scholar
  16. 16.
    Sperk G, Marksteiner J, Gruber B, Bellmann R, Mahata M, Ortler M. Functional changes in neuropeptide Y-and somatostatin-containing neurons induced by limbic seizures in the rat. Neurosci 1992, 50: 831–846.CrossRefGoogle Scholar
  17. 17.
    Sloviter RS. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the ‘dormant basket cell’ hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus1991, 1: 41–46.Google Scholar
  18. 18.
    Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol1989, 26: 321–330.Google Scholar
  19. 19.
    Cavazos JE, Golarai G, Sutula TP. Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence. J Neurosci 1991, 11: 2795–2803.PubMedGoogle Scholar
  20. 20.
    Masukawa LM, Higashiona M, Kim JH, Spencer DD. Epileptiform discharges evoked in hippocampal brain slices from epileptic patients. Brain Res 1989, 493: 168–174.PubMedCrossRefGoogle Scholar
  21. 21.
    Urban L, Aitken PG, Freidman A, Somjen GG. An NMDA-mediated component of excitatory synaptic input to dentate granule cells in ‘epileptic’ human hippocampus studied in vitro. Brain Res 1990, 515: 319–322.PubMedCrossRefGoogle Scholar
  22. 22.
    Sloviter RS. “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies. Brain Res Bull 1983, 10: 675–697.PubMedCrossRefGoogle Scholar
  23. 23.
    Johnson EW, De Lanerolle NC, Kim JH, Sundaresan S, Spencer DD, Mattson RH, Joghbi SS, Baldwin RM, Hoffer PB, Seibul JP, Innis RB. Central and peripheral benzodiazepine receptors: opposite changes in human epileptogenic tissue. Neurol 1992, 42: 811–815.CrossRefGoogle Scholar
  24. 24.
    Hosford DA, Crain BJ, Cao Z, Bonhaus DW, Friedman AH, Okazaki MM, Nadler JV, Mcnamara JO. Increased AMPA-sensitive quisqualate receptor binding and reduced NMD A receptor binding in epileptic human hippocampus. J Neurosci 1991, 11: 428–434.PubMedGoogle Scholar
  25. 25.
    Geddes JW, Cahan LD, Cooper SM, Kim RC, Choi BH, Cotman CW. Altered distribution of excitatory amino acid receptors in temporal lobe epilepsy. Exp Neurol 1990, 108: 214–220.PubMedCrossRefGoogle Scholar
  26. 26.
    Evans M, Griffiths T, Meldrum BS. Early changes in the rat hippocampus following seizures induced by bicuculline or L-allylglycine: a light and electron microscope study. Neuropathol Appl Neurobiol 1983, 9: 39–52.PubMedCrossRefGoogle Scholar
  27. 27.
    Griffiths T, Evans MC, Meldrum BS. Intracellular calcium accumulation in rat hippocampus during seizures induced by bicuculline or L-allylglycine. Neurosci 1983, 10: 385–395.CrossRefGoogle Scholar
  28. 28.
    Olney JW, De Gubareff T, Labruyere J. Seizure-related brain damage induced by cholinmnergic agents. Nature 1983, 301: 520–522.PubMedCrossRefGoogle Scholar
  29. 29.
    Sparenborg S, Brenneck LH, Jaax NK, Braitman DJ. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. Neuropharmacol 1992, 31: 357–368.CrossRefGoogle Scholar
  30. 30.
    Ben-ari Y, Tremblay E, Ottersen OP, Naquet R. Evidence suggesting secondary epileptogenic lesions after kainic acid: pretreatment with diazepam reduces distant but not local brain damage. Brain Res 1979, 165: 362–365.PubMedCrossRefGoogle Scholar
  31. 31.
    Unnerstall JR, Wamsley JK. Autoradiographic localization of high-affinity [3H] kainic acid binding sites in the rat forebrain. Eur J Pharmacol 1983, 86: 361–371.PubMedCrossRefGoogle Scholar
  32. 32.
    Ribak CE, Seress L, Amarai DG. The development, ultrastructure and synaptic connections of the mossy cells of the dentate gyrus. J Neurocytol 1985, 14: 835–857.PubMedCrossRefGoogle Scholar
  33. 33.
    Sloviter RS. Calcium-binding protein (Calbindin-D28k) and parvalbumin immunocy tochemistry: Localization in the rat hippocampus with specific reference to the selective vulnerability of hippocampal neurons to seizure activity. J Comp Neurol 1989, 280: 183–196.PubMedCrossRefGoogle Scholar
  34. 34.
    Scharfman HE, Schwartzkroin PA. Protection of dentate hilar cells from prolonged stimulation by intracellular calcium chelation. Science 1989, 246: 257–260.PubMedCrossRefGoogle Scholar
  35. 35.
    Freund TF, Ylinen A, Miettinen R, Pitkanen A, Lahtinen H, Baimbridge KG, Riekkinen PJ. Pattern of neuronal death in the rat hippocampus after status epilepticus. Relationship to calcium binding protein content and ischemic vulnerability. Brain Res Bull 1991, 28: 27–38.CrossRefGoogle Scholar
  36. 36.
    Scharfman HE, Schwartzkroin PA. Responses of cells of the rat fascia dentata to proonged stimulation of the perforant path: sensitivity of hilar cells and changes in granule cell excitability. Neuroscience 1990, 35: 491–504.PubMedCrossRefGoogle Scholar
  37. 37.
    Collins RC, Olney JW. Focal cortical seizures cause distant thalamic lesions. Science 1982, 218: 177–179.PubMedCrossRefGoogle Scholar
  38. 38.
    Olney JW, Degubareff T, Sloviter RS. “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. II. Ultrastructural analysis of acute hippocampal pathology. Brain Res Bull 1983, 10: 699–712.PubMedCrossRefGoogle Scholar
  39. 39.
    Fariello RG, Golden GT, Smith GG, Reyes PF. Potentiation of kainic acid epileptogenicity and sparing from neuronal damage by an NMDA receptor antagonist. Epilepsy Res 1989 3: 206–213.Google Scholar
  40. 40.
    Dragunow M, Preston K. The role of inducible transcription factors in apoptotic nerve cell death. Brain Res Rev 1995, 21: 1–28.PubMedCrossRefGoogle Scholar
  41. 41.
    Smeyne RJ, Vendrell M, Hayward M, Baker SJ, Miao GG, Schilling K, Robertson LM, Curran T, Morgan JI. Continuous c-fos expression precedes programmed cell death in vivo. Nature 1993, 363: 166–169.PubMedCrossRefGoogle Scholar
  42. 42.
    Manome Y, Datta R, Fine HA. Early response gene induction following DNA damage in astrocytoma cell lines. Biochem Pharmacol 1993, 45: 1677–1684.PubMedCrossRefGoogle Scholar
  43. 43.
    Colotta F, Polentarutti N, Sironi M, Mantovani A. Expression and involvement of c-fos and c-jun proto-oncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines. J Bio Chem 1992, 267: 18,278-18,283.Google Scholar
  44. 44.
    Morgan JI, Curran T. Proto-oncogene transcription factors and epilepsy. Trends Pharm Sci 1991, 12: 343–349.PubMedCrossRefGoogle Scholar
  45. 45.
    Shin C, Mcnamara JO, Morgan JI, Curran T, Cohen DR. Induction of c-fos mRNA expression by afterdischarges in the hippocampus of naive and kindled rats. J Neurochem 1990, 55: 1050–1055.PubMedCrossRefGoogle Scholar
  46. 46.
    Kiessling M, Stumm G, Xie Y, Herdegen T, Aguzzi A, Bravo R, Gass P. Differential transcription and translation of immediate early genes in the gerbil hippocampus after transient global ischemia. J Cereb Blood Flow Metab 1993, 13: 914–924.PubMedCrossRefGoogle Scholar
  47. 47.
    Dragunow M, Beilharz E, Sirimanne E, Lawlor P, Williams C, Bravo R, Gluckman P. Immediate early gene protein expression in neurons undergoing delayed death, but not necrosis, following hypoxic-ischemic injury to the young rat brain. Mol Brain Res 1994, 25: 19–23.PubMedCrossRefGoogle Scholar
  48. 48.
    Beilharz EJ, Williams Ce, Dragunow M, Sirimanne ES, Gluckman PD. Mechanisms of delayed cell death following hypoxic-ischemic injury in the immature rat: evidence for apoptosis during selective neuronal loss. Mol Brain Res 1995, 29: 1–14.PubMedCrossRefGoogle Scholar
  49. 49.
    Dragunow M, Young D, Hughes P, Macgibbon G, Lawlor P, Singleton K, Sirimanne E, Beilharz E, Gluckman P. Is c-jun involved in nerve cell death following status epilepticus and hypoxic-ischaemic brain injury? Mol Brain Res 1993, 18: 347–352.PubMedCrossRefGoogle Scholar
  50. 50.
    Coyle JT, Puttfarcken P. Oxidative stress, glutamate and neurodegenerative disorders. Science 1993, 262: 689–695.PubMedCrossRefGoogle Scholar
  51. 51.
    Schreiber SS, Baudry M. Selective vulnerability in the hippocampus—a role for gene expression? Trends Neurosci 1995, 18: 446–451.PubMedCrossRefGoogle Scholar
  52. 52.
    Neumann-Haefelin T, Wiebner C, Vogel P, Back T, Hossmann KA. Differential expression of the immediate early genes c-fos, c-jun, junB, and NGFI-B in the rat brain following transient forebrain ischemia. J Cereb Blood Flow Metab 1994, 14: 206–216.PubMedCrossRefGoogle Scholar
  53. 53.
    Sonnenberg JL, Mitchelmore C, Macgregor-Leon PF, Hempstead J, Morgan JI, Curan T. Glutamate receptor agonists increase the expression of Fos, Fra, and AP-1 DNA binding activity in the mammalian brain. J Neurosci Res 1989, 24: 72–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Schreiber SS, Tocco G, Najm I, Thompson RF, Baudry M. Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain. J Mol Neurosci 1993, 4: 149–159.PubMedCrossRefGoogle Scholar
  55. 55.
    Kure S, Tominaga T, Tada K, Narisawa K. Glutamate triggers internucleosomal DNA cleavage in neuronal cells. Biochem Biophy Res Commun 1991, 179: 39–45.CrossRefGoogle Scholar
  56. 56.
    Williams MB, Jope RS. Protein synthesis inhibitors attenuate seizures induced by lithium plus pilocarpine. Exp Neurol 1994, 129: 169–173.PubMedCrossRefGoogle Scholar
  57. 57.
    Leppin C, Finiels-Marlier F, Crawley JN, Montpied P, Paul SM. Failure of a protein synthesis inhibitor to modify glutamate receptor-mediated neurotoxicity in vivo. Brain Res 1992, 581: 168–170.PubMedCrossRefGoogle Scholar
  58. 58.
    Dessi F, Charriatu-Marlangue C, Khrestchatisky M, Ben-Ari Y. Glutamate-induced neuronal death is not a programmed cell death in cerebellar culture. J Neurochem 1993, 60: 1953–1955.PubMedCrossRefGoogle Scholar
  59. 59.
    Martin DP, Schmidt RE, Distefano PS, Lory Oh, Carter JG, Johnson EM. Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J Cell Biol 1988, 106: 829–844PubMedCrossRefGoogle Scholar
  60. 60.
    Pollard H, Charriaut-Marlangue C, Cantagrel S, Represa A, Robain O, Moreau J, Ben-Ari Y. Kainate-induced apoptotic cell death in hippocampal neurons. Neuroscience 1994, 63: 7–18.PubMedCrossRefGoogle Scholar
  61. 61.
    Finiels F, Robert JJ, Samolyk ML, Privat A, Mallet J, Revah F. Induction of neuronal apop-tosis by excitotoxins associated with long-lasting increase of 12-0-tetradecanoylphorbol 13-acetate-responsive element-binding activity. J Neurochem 1995, 65: 1027–1034.PubMedCrossRefGoogle Scholar
  62. 62.
    Ignatowicz E, Vezzani AM, Rizzi M, D’Incaici M. Nerve cell death induced in vivo by kainic acid and quinolinic acid does not involve apoptosis. NeuroReport 1991, 2: 651–654.PubMedCrossRefGoogle Scholar
  63. 63.
    Sun DY, Jiang S, Zheng LM, Ojcius DM, Young JDE. Separate metabolic pathways leading to DNA fragmentation and apoptotic chromatin condensation. J Exp Med 1994, 179: 559–568.PubMedCrossRefGoogle Scholar
  64. 64.
    Trump BG, Berezesky IK. Calcium-mediated cell injury and cell death. FASEB J 1995, 9: 219–228.PubMedGoogle Scholar
  65. 65.
    Oberhammer F, Wilson JE, Dive C, Morris ID, Hickman JA, Wakeling AE, Walker PR Sikorska M. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 1993, 12: 3679–3684.PubMedGoogle Scholar
  66. 66.
    Collins RJ, Harmon BV, Gobe GC, Kerr JFR. Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis. Int J Radiat Biol 1992, 61: 451–453.PubMedCrossRefGoogle Scholar
  67. 67.
    Clarke PGH. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol 1990, 181: 195–213.PubMedCrossRefGoogle Scholar
  68. 68.
    Sloviter RS, Dean E, Sollas AL, Goodman JH. Apoptosis and necrosis induced in different hippocampal neuron population by repetitive perforant path stimulation in the rat. J Comp Neurol 1996, 366: 516–533.PubMedCrossRefGoogle Scholar
  69. 69.
    Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. Apoptosis and necrosis: Two different events induced, respectively, by mild and intense insults with N-methyl-D-aspar-tate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 1995, 92: 7162–7166.PubMedCrossRefGoogle Scholar
  70. 70.
    Houser CR. GABA neurons in seizure disorder: A review of immunocytochemical studies. Neurochem Res 1991, 16: 295–308.PubMedCrossRefGoogle Scholar
  71. 71.
    Sloviter RS. The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy. Ann Neurol 1994, 35: 640–654.PubMedCrossRefGoogle Scholar
  72. 72.
    Schwartzkroin PA, Scharfman HE, Sloviter RS. Similarities in circuitry between Ammon’s horn and dentate gyrus: local interactions and parallel processing, in The Hippocampal Region as a Model for Studying Brain Structure and Function (Storm-Mathisen J, Zimmer J, Ottersen OP, eds.), Elsevier, NY, 1990, pp. 269–286.CrossRefGoogle Scholar
  73. 73.
    Tauck DL, Nadler JV. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci 1985, 5: 1016–1022.PubMedGoogle Scholar
  74. 74.
    Lowenstein DH, Thomas MJ, Smith DH, Mcintosh TK. Selective vulnerability of dentate hilar interneurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci 1991, 12: 4846–4853.Google Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Cheolsu Shin
  • Ki-Hyeong Lee

There are no affiliations available

Personalised recommendations