Chemoconvulsant Model of Chronic Spontaneous Seizures

Jennifer L. Hellier1, F. Edward Dudek2

1 University of Colorado Health Sciences Center, Denver, Colorado, 2 Colorado State University, Fort Collins, Colorado
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.19
DOI:  10.1002/0471142301.ns0919s31
Online Posting Date:  May, 2005
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

Animal models of injury‐induced epilepsy may provide insight into the mechanisms of acquired epilepsy. Previous animal models of temporal lobe epilepsy (TLE) were produced by acute treatments that often have high mortality rates and/or are associated with a low proportion of animals developing spontaneous, chronic motor seizures. In this unit, a protocol is provided for inducing chronic epilepsy in rats using multiple, low‐dose, intraperitoneal injections of an excitotoxic agent, kainic acid. This protocol reliably induces TLE in nearly all treated rats (97% had at least two observed spontaneous motor seizures) with a relatively low mortality rate (<15%). This modified chemoconvulsant treatment protocol (i.e., multiple low doses) is efficient and relatively simple, and the properties of the chronic epileptic state appear similar to those of severe human TLE.

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Basic Protocol 1: Kainate Induction of Chronic Spontaneous Seizures in Rats
  • Reagents and Solutions
  • Commentary
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

Basic Protocol 1: Kainate Induction of Chronic Spontaneous Seizures in Rats

  Materials
  • Male Sprague‐Dawley rats, 180 to 250 g (Harlan)
  • Tattoo dye (approved for animals) or ear‐piercing tool, optional
  • 2.5 mg/ml kainic acid in 0.9% (w/v) NaCl (see recipe)
  • 0.9% (w/v) NaCl (sterile saline)
  • Lactated Ringer's solution, 35°C
  • Apple slices and/or mashed rat chow
  • Animal scale
  • 35°C water bath or incubator
  • Standard rat cages (∼43‐cm length × 22‐cm width × 20‐cm height), with plastic lids approved by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC; e.g., Allentown Caging)
  • Disposable bed liners and/or paper towels
  • Syringes and needles suitable for intraperitoneal and subcutaneous injections
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Babb, T.L., Kupfer, W.R., Pretorius, J.K., Crandall, P.H., and Levesque, M.F. 1991. Synaptic reorganization by mossy fibers in human epileptic fascia dentata. Neuroscience 42:351‐363.
   Ben Ari, Y. 1985. Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375‐403.
   Bertram, E.H. and Cornett, J. 1993. The ontogeny of seizures in a rat model of limbic epilepsy: Evidence for a kindling process in the development of chronic spontaneous seizures. Brain Res. 625:295‐300.
   Bragin, A., Wilson, C.L., and Engel, J. Jr. 2000. Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: A hypothesis. Epilepsia 41(Suppl 6):S144‐S152.
   Buckmaster, P.S. and Dudek, F.E. 1997. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate‐treated rats. J. Comp. Neurol. 385:385‐404.
   Cavalheiro, E.A. 1995. The pilocarpine model of epilepsy. Ital. J. Neurol. Sci. 16:33‐37.
   Cavalheiro, E.A., Leite, J.P., Bortolotto, Z.A., Turski, W.A., Ikonomidou, C., and 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.
   Cavazos, J.E., Das, I., and Sutula, T.P. 1994. Neuronal loss induced in limbic pathways by kindling: Evidence for induction of hippocampal sclerosis by repeated brief seizures. J. Neurosci 14:3106‐3121.
   Cronin, J. and Dudek, F.E. 1988. Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res. 474:181‐184.
   Cronin, J., Obenaus, A., Houser, C.R., and Dudek, F.E. 1992. Electrophysiology of dentate granule cells after kainate‐induced synaptic reorganization of the mossy fibers. Brain Res. 573:305‐310.
   de Lanerolle, N.C., Kim, J.H., Robbins, R.J., and Spencer, D.D. 1989. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res. 495:387‐395.
   Engel, J.J. 1989. Seizures and Epilepsy. F.A. Davis, Philadelphia.
   Falconer, M.A. and Taylor, D.C. 1968. Surgical treatment of drug‐resistant epilepsy due to mesial temporal sclerosis. Etiology and significance. Arch. Neurol. 19:353‐361.
   French, J.A., Williamson, P.D., Thadani, V.M., Darcey, T.M., Mattson, R.H., Spencer, S.S., and Spencer, D.D. 1993. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann. Neurol. 34:774‐780.
   Glien, M., Brandt, C., Potschka, H., Voigt, H., Ebert, U., and Loscher, W. 2001. Repeated low‐dose treatment of rats with pilocarpine: Low mortality but high proportion of rats developing epilepsy. Epilepsy Res. 46:111‐119.
   Hellier, J.L. and Dudek, F.E. 1999. Spontaneous motor seizures of rats with kainate‐induced epilepsy: Effect of time of day and activity state. Epilepsy Res. 35:47‐57.
   Hellier, J.L., Patrylo, P.R., Buckmaster, P.S., and Dudek, F.E. 1998. Recurrent spontaneous motor seizures after repeated low‐dose systemic treatment with kainate: Assessment of a rat model of temporal lobe epilepsy. Epilepsy Res. 31:73‐84.
   Hellier, J.L., Patrylo, P.R., Dou, P., Nett, M., Rose, G.M., and Dudek, F.E. 1999. Assessment of inhibition and epileptiform activity in the septal dentate gyrus of freely behaving rats during the first week after kainate treatment. J. Neurosci. 19:10053‐10064.
   Hellier, J.L., Patrylo, P.R., Dou, P., Rose, G.M., Staley, K.J., and Dudek, F.E. 2000. Analysis of interictal‐to‐ictal transition in the dentate gyrus: Evidence for “breakdown of the dentate gate”. Epilepsia 41:44‐45.
   Houser, C.R., Miyashiro, J.E., Swartz, B.E., Walsh, G.O., Rich, J.R., and Delgado‐Escueta, A.V. 1990. Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy. J. Neurosci 10:267‐282.
   ILAE 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on classification and terminology of the International League Against Epilepsy. Epilepsia 30:389‐399.
   Loscher, W. 1997. Animal models of intractable epilepsy. Prog. Neurobiol. 53:239‐258.
   Lothman, E.W., Bertram, E.H., Kapur, J., and Stringer, J.L. 1990. Recurrent spontaneous hippocampal seizures in the rat as a chronic sequela to limbic status epilepticus. Epilepsy Res. 6:110‐118.
   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 89:499‐530.
   Mathern, G.W., Pretorius, J.K., and Babb, T.L. 1995. Quantified patterns of mossy fiber sprouting and neuron densities in hippocampal and lesional seizures. J. Neurosurg. 82:211‐219.
   McNamara, J.O. 1986. Kindling model of epilepsy. Adv. Neurol. 44:303‐318.
   Medvedev, A., Mackenzie, L., Hiscock, J.J., and Willoughby, J.O. 2000. Kainic acid induces distinct types of epileptiform discharge with differential involvement of hippocampus and neocortex. Brain Res. Bull. 52:89‐98.
   Mello, L.E., Cavalheiro, E.A., Tan, A.M., Kupfer, W.R., Pretorius, J.K., Babb, T.L., and Finch, D.M. 1993. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: Cell loss and mossy fiber sprouting. Epilepsia 34:985‐995.
   Nadler, J.V., Perry, B.W., and Cotman, C.W. 1980. Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3‐CA4 afferents with kainic acid. Brain Res. 182:1‐9.
   Racine, R.J. 1972. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32:281‐294.
   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 1:41‐66.
   Spencer, S.S. 2002. When should temporal‐lobe epilepsy be treated surgically? Lancet Neurol. 1:375‐382.
   Stafstrom, C.E., Thompson, J.L., and Holmes, G.L. 1992. Kainic acid seizures in the developing brain: Status epilepticus and spontaneous recurrent seizures. Brain Res. Dev. Brain Res. 65:227‐236.
   Sutula, T., Cascino, G., Cavazos, J., Parada, I., and Ramirez, L. 1989. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann. Neurol. 26:321‐330.
   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 3:154‐171.
   Turski, W.A., Cavalheiro, E.A., Schwarz, M., Czuczwar, S.J., Kleinrok, Z., and Turski, L. 1983. Limbic seizures produced by pilocarpine in rats: Behavioural, electroencephalographic and neuropathological study. Behav. Brain Res. 9:315‐335.
   Wasterlain, C.G., Shirasaka, Y., Mazarati, A.M., and Spigelman, I. 1996. Chronic epilepsy with damage restricted to the hippocampus: Possible mechanisms. Epilepsy Res. 26:255‐265.
   Williams, P.A., Wuarin, J.P., Dou, P., Ferraro, D.J., and Dudek, F.E. 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.
   Wozniak, D.F., Stewart, G.R., Miller, J.P., and Olney, J.W. 1991. Age‐related sensitivity to kainate neurotoxicity. Exp. Neurol. 114:250‐253.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library