Epilepsy, Brain Injury and Cell Death

  • Günther Sperk
  • Meinrad Drexel
  • Ramon Tasan
  • Anna Wieselthaler

Mesial temporal lobe epilepsy (TLE) represents the most frequent type of focal epilepsies. The most prominent neuropathological characteristics of TLE are severe neurodegenerations in the hippocampus (termed Ammon’s horn sclerosis) and in related brain areas such as the amygdala and entorhinal cortex. Within the hippocampus, pyramidal cells of the areas CA1 and CA3 and interneurons of the dentate hilus are most vulnerable, whereas granule cells of the dentate gyrus, CA2 pyramidal cells and the subiculum are comparatively preserved.


Granule Cell Status Epilepticus Dentate Gyrus Temporal Lobe Epilepsy Entorhinal Cortex 
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.

11. References

  1. Balchen, T., Berg, M. and Diemer, N.H., 1993, A paradox after systemic kainate injection in rats: lesser damage of hippocampal CA1 neurons after higher doses. Neurosci. Lett. 163: 151.CrossRefPubMedGoogle Scholar
  2. Ben-Ari, Y. and Cossart, R., 2000, Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci. 23: 580.CrossRefPubMedGoogle Scholar
  3. Bernard, C., Esclapez, M., Hirsch, J.C. and Ben-Ari, Y., 1998, Interneurones are not so dormant in temporal lobe epilepsy: a critical reappraisal of the dormant basket cell hypothesis. Epilepsy Res. 32: 93.CrossRefPubMedGoogle Scholar
  4. Blennow, G., Brierley, J.B., Meldrum, B.S., and Siesjo, B.K., 1978, Epileptic brain damage: the role of systemic factors that modify cerebral energy metabolism. Brain 101: 687.CrossRefPubMedGoogle Scholar
  5. Bouchet, C. and Cazauvieilh, A., 1825, De l’épilepsie consideré dans ses rappoert avec l’aleniénation mentale. Archives Générales de Medicine (Paris) 9: 519.Google Scholar
  6. Bouilleret, V., Ridoux, V., Depaulis, A., Marescaux, C., Nehlig, A. and Le Gal La Salle, G., 1999, Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience 89: 717.CrossRefPubMedGoogle Scholar
  7. Bratz, E., 1898, Ammonshornbefunde bei Epileptikern. Arch. Psychiatr. Nervenkrankh 32: 820.Google Scholar
  8. Browne, T.R. and Holmes, G.L., 2001, Epilepsy. N. Engl. J. Med. 344: 1145CrossRefPubMedGoogle Scholar
  9. Cendes, F., Andermann, F., Carpenter, S., Zatorre, R.J. and Cashman, N.R., 1995, Temporal lobe epilepsy caused by domoic acid intoxication: evidence for glutamate receptor-mediated excitotoxicity in humans. Ann. Neurol. 37: 123.CrossRefPubMedGoogle Scholar
  10. Choi, D.W., 1990, Cerebral hypoxia: some new approaches and unanswered questions. J. Neurosci. 10: 2493.PubMedGoogle Scholar
  11. Davenport, C.J., Brown, W.J. and Babb, T.L., 1990, Sprouting of GABAergic and mossy fiber axons in dentate gyrus following intrahippocampal kainate in the rat. Exp. Neurol. 109: 180.CrossRefPubMedGoogle Scholar
  12. Dube, C., Vezzani, A., Behrens, M., Bartfai, T. and Baram, T.Z., 2005, Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann. Neurol. 57: 152.CrossRefPubMedGoogle Scholar
  13. During, M.J. and Spencer, D.D., 1993, Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341: 1607.CrossRefPubMedGoogle Scholar
  14. Eid, T., Du, F. and Schwarcz, R., 2001, Ibotenate injections into the pre- and parasubiculum provide partial protection against kainate-induced epileptic damage in layer III of rat entorhinal cortex. Epilepsia 42: 817.CrossRefPubMedGoogle Scholar
  15. Engel, J., Jr., 1996, Introduction to temporal lobe epilepsy. Epilepsy Res. 26: 141.CrossRefPubMedGoogle Scholar
  16. Faherty, C.J., Xanthoudakis, S. and Smeyne, R.J., 1999, Caspase-3-dependent neuronal death in the hippocampus following kainic acid treatment. Brain Res. Mol. Brain Res. 70: 159.CrossRefPubMedGoogle Scholar
  17. Finsen, B.R., Jorgensen, M.B., Diemer, N.H. and Zimmer, J., 1993, Microglial MHC antigen expression after ischemic and kainic acid lesions of the adult rat hippocampus. Glia 7: 41.CrossRefPubMedGoogle Scholar
  18. Frotscher, M., Haas, C.A. and Forster, E., 2003, Reelin controls granule cell migration in the dentate gyrus by acting on the radial glial scaffold. Cereb. Cortex 13: 634.CrossRefPubMedGoogle Scholar
  19. Furtinger, S., Pirker, S., Czech, T., Baumgartner, C., Ransmayr, G. and Sperk, G., 2001, Plasticity of Y1 and Y2 receptors and neuropeptide Y fibers in patients with temporal lobe epilepsy. J. Neurosci. 21: 5804.PubMedGoogle Scholar
  20. Gall, C., Lauterborn, J., Bundman, M., Murray, K. and Isackson, P., 1991, Seizures and the regulation of neurotrophic factor and neuropeptide gene expression in brain. Epilepsy Res. 4 suppl: 225.CrossRefGoogle Scholar
  21. Gillardon, F., Wickert, H. and Zimmermann, M., 1995, Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain. Neurosci. Lett. 192: 85.CrossRefPubMedGoogle Scholar
  22. Guthrie, K.M., Woods, A.G., Nguyen, T. and Gall, G.M., 1997, Astroglial ciliary neurotrophic factor mRNA expression is increased in fields of axonal sprouting in deafferented hippocampus. J. Comp. Neurol. 386: 137.CrossRefPubMedGoogle Scholar
  23. Haas, C.A., Dudeck, O., Kirsch, M., Huszka, C., Kann, G., Pollak, S., Zentner, J. and Frotscher, M., 2002, Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J. Neurosci. 22: 5797.PubMedGoogle Scholar
  24. Henshall, D.C. and Simon, R.P., 2005, Epilepsy and apoptosis pathways. J. Cereb. Blood Flow Metab. 25: 1557.CrossRefPubMedGoogle Scholar
  25. Herdegen, T., Sandkuhler, J., Gass, P., Kiessling, M., Bravo, R. and Zimmermann, M., 1993, JUN, FOS, KROX, and CREB transcription factor proteins in the rat cortex: basal expression and induction by spreading depression and epileptic seizures. J. Comp. Neurol. 333: 271.CrossRefPubMedGoogle Scholar
  26. Houser, C.R., 1990, Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res. 535: 195.CrossRefPubMedGoogle Scholar
  27. Iadecola, C., 1997, Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci. 20: 132.CrossRefPubMedGoogle Scholar
  28. Jensen, M.B., Finsen, B. and Zimmer, J., 1997, Morphological and immunophenotypic microglial changes in the denervated fascia dentata of adult rats: correlation with blood-brain barrier damage and astroglial reactions. Exp. Neurol. 143: 103.CrossRefPubMedGoogle Scholar
  29. Jorgensen, M.B., Finsen, B.R., Jensen, M.B., Castellano, B., Diemer, N.H. and Zimmer, J., 1993, Microglial and astroglial reactions to ischemic and kainic acid-induced lesions of the adult rat hippocampus. Exp. Neurol. 120: 70.CrossRefPubMedGoogle Scholar
  30. Lassmann, H., Petsche, U., Kitz, K., Baran, H., Sperk, G., Seitelberger, F. and Hornykiewicz, O., 1984, The role of brain edema in epileptic brain damage induced by systemic kainic acid injection. Neuroscience 13: 691.CrossRefPubMedGoogle Scholar
  31. Laurberg, S. and Zimmer, J., 1981, Lesion-induced sprouting of hippocampal mossy fiber collaterals to the fascia dentata in developing and adult rats. J. Comp. Neurol. 200: 433.CrossRefPubMedGoogle Scholar
  32. Lehmann, A., 1987, Alterations in hippocampal extracellular amino acids and purine catabolites during limbic seizures induced by folate injections into the rabbit amygdala. Neuroscience 22: 573.CrossRefPubMedGoogle Scholar
  33. Lehmann, T.N., Gabriel, S., Eilers, A., Njunting, M., Kovacs, R., Schulze, K., Lanksch, W.R. and Heinemann, U., 2001, Fluorescent tracer in pilocarpine-treated rats shows widespread aberrant hippocampal neuronal connectivity. Eur. J. Neurosci. 14: 83.CrossRefPubMedGoogle Scholar
  34. Liu, Z., Mikati, M. and Holmes, G.L., 1995, Mesial temporal sclerosis: pathogenesis and significance. Pediatr. Neurol. 12: 5CrossRefPubMedGoogle Scholar
  35. Lothman, E.W., Bertram, E.H., Bekenstein, J.W. and Perlin, J.B., 1989, Self-sustaining limbic status epilepticus induced by ‘continuous’ hippocampal stimulation: electrographic and behavioral characteristics. Epilepsy Res. 3:107.CrossRefPubMedGoogle Scholar
  36. Lowenstein, D.H. and Alldredge, B.K., 1998, Status epilepticus. N. Engl. J. Med. 338: 970.CrossRefPubMedGoogle Scholar
  37. Lowenstein, D.H., Thomas, M.J., Smith, D.H. and McIntosh, T.K., 1992, Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J. Neurosci. 12: 4846.PubMedGoogle Scholar
  38. Margerison, J.H. and Corsellis, J.A., 1966, Epilepsy and the temporal lobes. A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain 89: 499.CrossRefPubMedGoogle Scholar
  39. Mathern, G.W., Babb, T.L., Pretorius, J.K. and Leite, J.P., 1995, Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentata. J. Neurosci. 15: 3990.PubMedGoogle Scholar
  40. Meldrum, B.S., 1993, Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol. 3: 405.CrossRefPubMedGoogle Scholar
  41. Mellanby, J., Hawkins, C., Mellanby, H., Rawlins, J.N. and Impey, M.E., 1984, Tetanus toxin as a tool for studying epilepsy. J. Physiol. (Paris) 79: 207.Google Scholar
  42. Mikkonen, M., Soininen, H., Kalvianen, R., Tapiola, T., Ylinen, A., Vapalahti, M., Paljarvi, L. and Pitkanen, A., 1998, Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex. Ann. Neurol. 44: 923.CrossRefPubMedGoogle Scholar
  43. Mitchell, J., Sundstrom, L.E. and Wheal, H.V., 1993, Microglial and astrocytic cell responses in the rat hippocampus after an intracerebroventricular kainic acid injection. Exp. Neurol. 121: 224.CrossRefPubMedGoogle Scholar
  44. Mody, I. and MacDonald, J.F., 1995, NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release. Trends Pharmacol. Sci. 16: 356.CrossRefPubMedGoogle Scholar
  45. Morgan, J.I. and Curran, T., 1991, Proto-oncogene transcription factors and epilepsy. Trends Pharmacol. Sci. 12: 343.CrossRefPubMedGoogle Scholar
  46. Nagata, S., 1997, Apoptosis by death factor. Cell 88: 355.CrossRefPubMedGoogle Scholar
  47. Nakic, M., Mitrovic, N., Sperk, G. and Schachner, M., 1996, Kainic acid activates transient expression of tenascin-C in the adult rat hippocampus. J. Neurosci. Res. 44: 355.CrossRefPubMedGoogle Scholar
  48. Nissinen, J., Halonen, T., Koivisto, E. and Pitkanen, A., 2000, A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res. 38: 177.CrossRefPubMedGoogle Scholar
  49. Nitsch, C. and Hubauer, H., 1986, Distant blood-brain barrier opening in subfields of the rat hippocampus after intrastriatal injections of kainic acid but not ibotenic acid. Neurosci. Lett. 64: 53.CrossRefPubMedGoogle Scholar
  50. Orrenius, S., Zhivotovsky, B. and Nicotera, P., 2003, Regulation of cell death: the calcium-apoptosis link. Nat. Rev. Mol. Cell. Biol. 4: 552.CrossRefPubMedGoogle Scholar
  51. Pellegrini-Giampietro, D.E., Gorter, J.A., Bennett, M.V. and Zukin, R.S., 1997, The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci. 20: 464.CrossRefPubMedGoogle Scholar
  52. Perez, Y., Morin, F., Beaulieu, C. and Lacaille, J.C., 1996, Axonal sprouting of CA1 pyramidal cells in hyperexcitable hippocampal slices of kainate-treated rats. Eur. J. Neurosci. 8: 736.CrossRefPubMedGoogle Scholar
  53. Pirker, S., Czech, T., Baumgartner, C., Maier, H., Novak, K., Furtinger, S., Fischer-Colbrie, R. and Sperk, G., 2001, Chromogranins as markers of altered hippocampal circuitry in temporal lobe epilepsy. Ann. Neurol. 50: 216.CrossRefPubMedGoogle Scholar
  54. Pollard, H., Charriaut-Marlangue, C., Cantagrel, S., Represa, A., Robain, O., Moreau, J. and Ben-Ari, Y., 1994, Kainate-induced apoptotic cell death in hippocampal neurons. Neuroscience 63: 7.CrossRefPubMedGoogle Scholar
  55. Polster, B.M. and Fiskum, G., 2004, Mitochondrial mechanisms of neural cell apoptosis. J. Neurochem. 90: 1281.CrossRefPubMedGoogle Scholar
  56. Represa, A., Niquet, J., Charriaut-Marlangue, C. and Ben-Ari, Y., 1993, Reactive astrocytes in the kainic acid-damage hippocampus have the phenotypic features of type-2 astrocytes. J. Neurocytol. 22: 299.CrossRefPubMedGoogle Scholar
  57. Scharfman, H.E., 1991, Dentate hilar cells with dendrites in the molecular layer have lower thresholds for synaptic activation by perforant path than granule cells. J. Neurosci. 11: 1660.PubMedGoogle Scholar
  58. Seifert, G., Huttmann, K., Schramm, J. and Steinhauser, C., 2004, Enhanced relative expression of glutamate receptor 1 flip AMPA receptor subunits in hippocampal astrocytes of epilepsy patients with Ammon’s horn sclerosis. J. Neurosci. 24: 1996.CrossRefPubMedGoogle Scholar
  59. Seki, T. and Rutishauser, U., 1998, Removal of polysialic acid-neural cell adhesion molecule induces aberrant mossy fiber innervation and ectopic synaptogenesis in the hippocampus. J. Neurosci. 18: 3757.PubMedGoogle Scholar
  60. Siesjo, B.K. and Wieloch, T., 1986, Epileptic brain damage: pathophysiology and neurochemical pathology. Adv. Neurol. 44: 813.PubMedGoogle Scholar
  61. Simon, R.P., Schmidley, J.W., Meldrum, B.S., Swan, J.H. and Chapman, A.G., 1986, Excitotoxic mechanisms in hypoglycaemic hippocampal injury. Neuropathol. Appl. Neurobiol. 12: 567.CrossRefPubMedGoogle Scholar
  62. Skulachev, V.P., 1998, Cytochrome c in the apoptotic and antioxidant cascades. FEBS Lett. 423: 275.CrossRefPubMedGoogle Scholar
  63. Sloviter, R.S., 1983, Epileptic brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies. Brain Res. Bull. 10: 675.CrossRefPubMedGoogle Scholar
  64. Sloviter, R.S., 1991, 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. Hippocampus 1: 41.CrossRefPubMedGoogle Scholar
  65. Sloviter, R.S. and Dempster, D.W., 1985, Epileptic brain damage is replicated qualitatively in the rat hippocampus by central injection of glutamate or aspartate but not by GABA or acetylcholine. Brain Res. Bull. 15: 39.CrossRefPubMedGoogle Scholar
  66. Sloviter, R.S., Zappone, C.A., Harvey, B.D., Bumanglag, A.V., Bender, R.A. and Frotscher, M., 2003, Dormant basket cell hypothesis revisited: relative vulnerabilities of dentate gyrus mossy cells and inhibitory interneurons after hippocampal status epilepticus in the rat. J. Comp. Neurol. 459: 44.CrossRefPubMedGoogle Scholar
  67. Sommer, W., 1880, Erkrankung des Ammonshornes als ätiologisches Moment der Epilepsie. Arch. Psychiatr. Nervenkrankh. 10: 631.CrossRefGoogle Scholar
  68. Sperk, G., 1994, Kainic acid seizures in the rat. Prog. Neurobiol. 42: 1.CrossRefPubMedGoogle Scholar
  69. Sperk, G., Lassmann, H., Baran, H., Kish, S.J., Seitelberger, F. and Hornykiewicz, O., 1983, Kainic acid induced seizures: Neurochemical and histopathological changes. Neuroscience 10: 1301.CrossRefPubMedGoogle Scholar
  70. Sperk, G., Marksteiner, J., Gruber, B., Bellmann, R., Mahata, M. and Ortler, M. 1992, Functional changes in neuropeptide Y- and somatostatin-containing neurons induced by limbic seizures in the rat. Neuroscience 50: 831.CrossRefPubMedGoogle Scholar
  71. Sperk, G., Furtinger, S., Schwarzer, C. and Pirker, S., 2004, GABA and its receptors in epilepsy. Adv. Exp. Med. Biol. 548: 92.PubMedGoogle Scholar
  72. Spielmeyer, W., 1927, Die Pathogenese des epileptischen Krampfes. Z. ges Neurol. Psychiatr. 109: 501.Google Scholar
  73. Sutula, T., Xiao-Xian, H., Cavazos, J. and Scott, G., 1988, Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 239: 1147.CrossRefPubMedGoogle Scholar
  74. Sutula, T., Cascino, G., Cavazos, J., Parada, I. and Ramirez, L., 1989, Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann. Neurol. 26: 321.CrossRefPubMedGoogle Scholar
  75. Tanaka, T., Tanaka, S., Fujita, T., Takano, K., Fukuda, H., Sako, K. and Yonemasu, Y., 1992, Experimental complex partial seizures induced by a microinjection of kainic acid into limbic structures. Prog. Neurobiol. 38: 317.CrossRefPubMedGoogle Scholar
  76. Teitelbaum, J.S., Zatorre, R.J., Carpenter, S., Gendron, D., Evans, A.C., Gjedde, A., and Cashman, N.R., 1990, Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N. Engl. J. Med. 322: 1781.PubMedCrossRefGoogle Scholar
  77. Treiman, D.M., Meyers, P.D., Walton, N.Y., Collins, J.F., Colling, C., Rowan, A.J., Handforth, A., Faught, E., Calabrese, V.P., Uthman, B.M., Ramsay, R.E. and Mamdani, M.B., 1998, A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N. Engl. J. Med. 339: 792.CrossRefPubMedGoogle Scholar
  78. Turski, L., Ikonomidou, C., Turski, W.A., Bortolotto, Z.A. and Cavalheiro, E.A., 1989, Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse 3: 154.CrossRefPubMedGoogle Scholar
  79. Vezzani, A., Sperk, G. and Colmers, W.F., 1999, Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci. 22: 25.CrossRefPubMedGoogle Scholar
  80. Wu, H.Q., Turski, W.A., Ungerstedt, U. and Schwarcz, R., 1991, Systemic kainic acid administration in rats: effects on kynurenic acid production in vitro and in vivo. Exp. Neurol. 113: 47.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Günther Sperk
    • 1
  • Meinrad Drexel
    • 1
  • Ramon Tasan
    • 1
  • Anna Wieselthaler
    • 1
  1. 1.Department of PharmacologyInnsbruck Medical UniversityAustria

Personalised recommendations