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Neurochemical Research

, Volume 42, Issue 7, pp 1873–1888 | Cite as

Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs

  • Wolfgang LöscherEmail author
Original Paper

Abstract

The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.

Keywords

Antiepileptic drug Drug screening Anticonvulsant screening project Fit-for-purpose models 

Abbreviations

ADD

Antiepileptic drug development

ASD

Antiseizure drugs

ASP

Anticonvulsant Screening Project

CNS

Central nervous system

ECB

External Consultant Board

EST

Electroshock threshold

ETSP

Epilepsy Therapy Screening Program

GAERS

Genetic Absence Epilepsy Rat from Strasbourg

MES

Maximal electroshock seizure

NIH

National Institutes of Health

NINDS

National Institutes of Neurological Disorders and Stroke

NMDA

N-methyl-d-aspartate

PANAChE

Public access to neuroactive and anticonvulsant chemical evaluations

P-gp

P-glycoprotein

PTZ

Pentylenetetrazole

s.c.

Subcutaneous

SRS

Spontaneous recurrent seizures

TBI

Traumatic brain injury

TLE

Temporal lobe epilepsy

Notes

Acknowledgements

I thank my colleagues and friends Harvey Kupferberg and Steve White for critically reading a first version of this review and John Kehne for providing Fig. 4. WL is a member of the External Consultant Board (ECB) of the ETSP and thanks the other ECB members and all colleagues from the NINDS Epilepsy Branch and ETSP contract site in Utah for fruitful discussions on how to improve ASD discovery. The author’s own studies have been supported by grants from the German Research Foundation (DFG, Bonn, Germany; Grant # LO 274/1 - LO 274/16), the National Institutes of Health (NIH; Bethesda, MD, USA: Grant # R21 NS049592-01), the European Union’s Seventh Framework Programme (FP7) under grant agreements 201380 (EURIPIDES) and 602102 (EPITARGET), and the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony in Germany.

References

  1. 1.
    Bialer M, White HS (2010) Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9:68–82PubMedCrossRefGoogle Scholar
  2. 2.
    Löscher W, Klitgaard H, Twyman RE, Schmidt D.(2013) New avenues for antiepileptic drug discovery and development. Nat Rev Drug Discov 12:757–776PubMedCrossRefGoogle Scholar
  3. 3.
    Putnam TJ, Merritt HH (1937) Experimental determination of the anticonvulsant properties of some phenyl derivatives. Science 85:525–526PubMedCrossRefGoogle Scholar
  4. 4.
    Löscher W (2016) Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res 126:157–184PubMedCrossRefGoogle Scholar
  5. 5.
    Löscher W, Schmidt D (2011) Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52:657–678PubMedCrossRefGoogle Scholar
  6. 6.
    French JA, White HS, Klitgaard H, Holmes GL, Privitera MD, Cole AJ, Quay E, Wiebe S, Schmidt D, Porter RJ, Arzimanoglou A, Trinka E, Perucca E (2013) Development of new treatment approaches for epilepsy: unmet needs and opportunities. Epilepsia 54(Suppl 4):3–12PubMedCrossRefGoogle Scholar
  7. 7.
    O’Brien TJ, Ben Menachem E, Bertram EH III, Collins SD, Kokaia M, Lerche H, Klitgaard H, Staley KJ, Vaudano E, Walker MC, Simonato M (2013) Proposal for a “phase II” multicenter trial model for preclinical new antiepilepsy therapy development. Epilepsia 54(Suppl 4):70–74PubMedCrossRefGoogle Scholar
  8. 8.
    Wilcox KS, Dixon-Salazar T, Sills GJ, Ben Menachem E, White HS, Porter RJ, Dichter MA, Moshe SL, Noebels JL, Privitera MD, Rogawski MA (2013) Issues related to development of new antiseizure treatments. Epilepsia 54(Suppl 4):24–34PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Harward SC, McNamara JO (2014) Aligning animal models with clinical epilepsy: where to begin? Adv Exp Med Biol 813:243–251PubMedCrossRefGoogle Scholar
  10. 10.
    Simonato M, Brooks-Kayal AR, Engel J Jr, Galanopoulou AS, Jensen FE, Moshe SL, O’Brien TJ, Pitkänen A, Wilcox KS, French JA (2014) The challenge and promise of anti-epileptic therapy development in animal models. Lancet Neurol 13:949–960PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Grone BP, Baraban SC (2015) Animal models in epilepsy research: legacies and new directions. Nat Neurosci 18:339–343PubMedCrossRefGoogle Scholar
  12. 12.
    Purpura DP, Penry JK, Tower D, Woodbury DM, Walter R (1972) Experimental models of epilepsy—A manual for the laboratory worker. Raven Press, New YorkGoogle Scholar
  13. 13.
    Krall RL, Penry JK, Kupferberg HJ, Swinyard EA (1978) Antiepileptic drug development: I. History and a program for progress. Epilepsia 19:393–408PubMedCrossRefGoogle Scholar
  14. 14.
    Friedlander WJ (1986) Putnam, Merritt, and the discovery of Dilantin. Epilepsia 27(Suppl 3):S1–S20PubMedCrossRefGoogle Scholar
  15. 15.
    Kupferberg H (2001) Animal models used in the screening of antiepileptic drugs. Epilepsia 42(Suppl 4):7–12PubMedCrossRefGoogle Scholar
  16. 16.
    White HS (2003) Preclinical development of antiepileptic drugs: past, present, and future directions. Epilepsia 44(Suppl 7):2–8PubMedCrossRefGoogle Scholar
  17. 17.
    Kaminski HJ (2009) The legacy of Tracy J. Putnam and H. Houston Merritt: modern neurology in the United States. New Engl J Med 360:941–942CrossRefGoogle Scholar
  18. 18.
    Shorvon SD (2009) Drug treatment of epilepsy in the century of the ILAE: the first 50 years, 1909–1958. Epilepsia 50(Suppl 3):69–92PubMedCrossRefGoogle Scholar
  19. 19.
    Shorvon SD (2009) Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959–2009. Epilepsia 50(Suppl 3):93–130PubMedCrossRefGoogle Scholar
  20. 20.
    Arzimanoglou A, Ben-Menachem E, Cramer J, Glauser T, Seeruthun R, Harrison M (2010) The evolution of antiepileptic drug development and regulation. Epileptic Disord 12:3–15PubMedGoogle Scholar
  21. 21.
    Brodie MJ (2010) Antiepileptic drug therapy the story so far. Seizure 19:650–655PubMedCrossRefGoogle Scholar
  22. 22.
    Sidiropoulou K, Diamantis A, Magiorkinis E (2010) Hallmarks in 18th- and 19th-century epilepsy research. Epilepsy Behav 18:151–161PubMedCrossRefGoogle Scholar
  23. 23.
    White HS, Johnson M, Wolf HH, Kupferberg HJ (1995) The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models. Ital J Neurol Sci 16:73–77PubMedCrossRefGoogle Scholar
  24. 24.
    White HS (1997) Clinical significance of animal seizure models and mechanism of action studies of potential antiepileptic drugs. Epilepsia 38:S9–S17PubMedCrossRefGoogle Scholar
  25. 25.
    White HS (1999) Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia 40:S2–S10PubMedCrossRefGoogle Scholar
  26. 26.
    White HS (2002) Animal models of epileptogenesis. Neurology 59:S7–S14PubMedCrossRefGoogle Scholar
  27. 27.
    White HS, Smith-Yockman M, Srivastava A, Wilcox KS (2006) Therapeutic assays for the identification and characterization of antiepileptic and antiepileptogenic drugs. In: Pitkänen A, Schwartzkroin PA, and Moshé SL (eds.), Models of seizures and epilepsy. Elsevier, Amsterdam, pp 539–549CrossRefGoogle Scholar
  28. 28.
    White HS, Wolf HH, Woodhead JH, Kupferberg HJ (1998) The National Institutes of Health Anticonvulsant Drug Development Program: screening for efficacy. Adv Neurol 76:29–39PubMedGoogle Scholar
  29. 29.
    Rowley NM, White HS (2010) Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: correlation with other seizure and epilepsy models. Epilepsy Res 92:163–169PubMedCrossRefGoogle Scholar
  30. 30.
    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 69:1210–1219PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    White HS (2012) Animal models for evaluating antiepileptogenesis. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, and Delgado-Escueta AV (eds.), Jasper’s Basic Mechanisms of the Epilepsies, 4th edition. Oxford University Press, New York, pp 1041–1054CrossRefGoogle Scholar
  32. 32.
    Srivastava AK, White HS (2013) Carbamazepine, but not valproate, displays pharmacoresistance in lamotrigine-resistant amygdala kindled rats. Epilepsy Res 104:26–34PubMedCrossRefGoogle Scholar
  33. 33.
    Thomson KE, White HS (2014) A novel open-source drug-delivery system that allows for first-of-kind simulation of nonadherence to pharmacological interventions in animal disease models. J Neurosci Methods 238:105–111PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    White HS, Löscher W (2014) Searching for the ideal antiepileptogenic agent in experimental models: single treatment versus combinatorial treatment strategies. Neurother 11:373–384CrossRefGoogle Scholar
  35. 35.
    Barker-Haliski ML, Dahle EJ, Heck TD, Pruess TH, Vanegas F, Wilcox KS, White HS (2015) Evaluating an etiologically relevant platform for therapy development for temporal lobe epilepsy: effects of carbamazepine and valproic acid on acute seizures and chronic behavioral comorbidities in the Theiler’s murine encephalomyelitis virus mouse model. J Pharmacol Exp Ther 353:318–329PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Barker-Haliski ML, Heck TD, Dahle EJ, Vanegas F, Pruess TH, Wilcox KS, White HS (2016) Acute treatment with minocycline, but not valproic acid, improves long-term behavioral outcomes in the Theiler’s virus model of temporal lobe epilepsy. Epilepsia 57:1958–1967PubMedCrossRefGoogle Scholar
  37. 37.
    Barton ME, Klein BD, Wolf HH, White HS (2001) Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res 47:217–228PubMedCrossRefGoogle Scholar
  38. 38.
    Löscher W, Rogawski MA (2012) How theories evolved concerning the mechanism of action of barbiturates. Epilepsia 53(Suppl 8):12–25PubMedCrossRefGoogle Scholar
  39. 39.
    Hauptmann A (1912) Luminal bei Epilepsie. Münch Med Wochenschr 59:1907–1909Google Scholar
  40. 40.
    Blum E (1932) Die Bekämpfung epileptischer Anfälle und ihrer Folgeerscheinungen mit Prominal. Dtsch Med Wochenschr 58:696–698CrossRefGoogle Scholar
  41. 41.
    Weese H (1932) Pharmakologie des Prominal. Dtsch Med Wochenschr 58:696CrossRefGoogle Scholar
  42. 42.
    Page LGM (1936) Prominal in epilepsy. Br Med J 1:531Google Scholar
  43. 43.
    Millman CG (1939) Report on five years’ use of prominal as routine treatment for epileptics. J Ment Sci 85:971–975Google Scholar
  44. 44.
    Albertoni P (1882) Untersuchungen über die Wirkung einiger Arzneimittel auf die Erregbarkeit des Grosshirns nebst Beiträgen zur Therapie der Epilepsie. Arch Exp Pathol Pharmakol 15:248–288CrossRefGoogle Scholar
  45. 45.
    Hildebrandt F (1926) Pentamethylentetrazol (Cardiazol). I. Mitteilung. Naunyn-Schmiedeberg’s Arch Exp Pathol Pharmacol 116:100–109CrossRefGoogle Scholar
  46. 46.
    Spiegel EA (1937) Quantitative determination of the convulsive reactivity by electrical stimulation of the brain with the skull intact. J Lab Clin Med 22:1274–1276Google Scholar
  47. 47.
    Merritt HH, Putnam TJ, Schwab DM (1938) A new series of anticonvulsant drugs tested by experiments on animals. Arch Neurol Psychiatry 39:1003–1015CrossRefGoogle Scholar
  48. 48.
    Merritt HH, Putnam TJ (1938) Sodium diphenyl hydantoinate in the treatment of convulsive disorders. JAMA 111:1068–1073CrossRefGoogle Scholar
  49. 49.
    Toman JEP, Swinyard EA, Goodman LS (1946) Properties of maximal seizures and their alteration by anticonvulsant drugs and other agents. J Neurophysiol 9:231–239PubMedGoogle Scholar
  50. 50.
    Everett GM, Richards RK (1944) Comparative anticonvulsive action of 3,5,5-trimethyloxazolidine-2,4-dione (Tridione), Dilantin and phenobarbital. J Pharmacol Exp Ther 81:402–407Google Scholar
  51. 51.
    Swinyard EA (1949) Laboratory assay of clinically effective antiepileptic drugs. J Am Pharm Assoc 38:201–204CrossRefGoogle Scholar
  52. 52.
    Swinyard EA, Brown WC, Goodman LS (1952) Comparative assay of antiepileptic drugs in mice and rats. J Pharmacol Exp Ther 106:319–330PubMedGoogle Scholar
  53. 53.
    Chen G, Portman R, Ensor CR, Bratton AC Jr (1951) The anticonvulsant activity of o-phenyl succinimides. J Pharmacol Exp Ther 103:54–61PubMedGoogle Scholar
  54. 54.
    Porter RJ, Kupferberg HJ (2017) The anticonvulsant screening program of the National Institute of Neurological Disorders and Stroke, NIH: history and contributions to clinical care in the 20th century and beyond. Neurochem Res (in press)Google Scholar
  55. 55.
    Löscher W, Schmidt D (2012) Seizing the moment for the future: the U.S. Anticonvulsant Screening Project. Epilepsia 53:1841–1842PubMedCrossRefGoogle Scholar
  56. 56.
    Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA (1978) Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia 19:409–428PubMedCrossRefGoogle Scholar
  57. 57.
    Kehne JH (2017) National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP). Neurochem Res (in press)Google Scholar
  58. 58.
    Metcalf C, West P, Rueda C, Thomson K, Lu Z, Smith M, Wilcox K (2016) Development and pharmacologic characterization of the rat 6 HZ model. American Epilepsy Society 70th Annual Meeting Abstracts Online Abst. 1.058.Google Scholar
  59. 59.
    Barker-Haliski ML, Johnson K, Billingsley P, Huff J, Handy LJ, Khaleel R, Lu Z, Mau MJ, Pruess TH, Rueda C, Saunders G, Underwood TK, Vanegas F, Smith MD, West PJ, Wilcox KS (2017) Validation of a preclinical testing platform for pharmacoresistant epilepsy. Neurochem Res (in press)Google Scholar
  60. 60.
    Vezzani A, Fujinami RS, White HS, Preux PM, Blümcke I, Sander JW, Löscher W (2016) Infections, inflammation and epilepsy. Acta Neuropathol 131:211–234PubMedCrossRefGoogle Scholar
  61. 61.
    Toman JEP (1951) Experimental psychomotor seizures. Electroencephalogr Clin Neurophysiol 3:253CrossRefGoogle Scholar
  62. 62.
    Goddard GV, McIntyre DC, Leech CK (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25:295–330PubMedCrossRefGoogle Scholar
  63. 63.
    Sato M, Racine RJ, McIntyre DC (1990) Kindling: basic mechanisms and clinical validity. Electroenceph Clin Neurophysiol 76:459–472PubMedCrossRefGoogle Scholar
  64. 64.
    Löscher W, Jäckel R, Czuczwar SJ (1986) Is amygdala kindling in rats a model for drug-resistant partial epilepsy? Exp Neurol 93:211–226PubMedCrossRefGoogle Scholar
  65. 65.
    Löscher W, Brandt C (2010) Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev 62:668–700PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Löscher W, Rundfeldt C (1991) Kindling as a model of drug-resistant partial epilepsy: selection of phenytoin-resistant and nonresistant rats. J Pharmacol Exp Ther 258:483–489PubMedGoogle Scholar
  67. 67.
    Sangdee P, Turkanis SA, Karler R (1982) Kindling-like effect induced by repeated corneal electroshock in mice. Epilepsia 23:471–479PubMedCrossRefGoogle Scholar
  68. 68.
    Matagne A, Klitgaard H (1998) Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man. Epilepsy Res 31:59–71PubMedCrossRefGoogle Scholar
  69. 69.
    Potschka H, Löscher W (1999) Corneal kindling in mice: behavioral and pharmacological differences to conventional kindling. Epilepsy Res 37:109–120PubMedCrossRefGoogle Scholar
  70. 70.
    Löscher W, Hönack D (1991) Responses to NMDA receptor antagonists altered by epileptogenesis. Trends Pharmacol Sci 12:52PubMedCrossRefGoogle Scholar
  71. 71.
    Sveinbjornsdottir S, Sander JWAS, Upton D, Thompson PJ, Patsalos PN, Hirt D, Emre M, Lowe D, Duncan JS (1993) The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res 16:165–174PubMedCrossRefGoogle Scholar
  72. 72.
    Leclercq K, Matagne A, Kaminski RM (2014) Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model. Epilepsy Res 108:675–683PubMedCrossRefGoogle Scholar
  73. 73.
    Levesque M, Avoli M, Bernard C (2016) Animal models of temporal lobe epilepsy following systemic chemoconvulsant administration. J Neurosci Methods 260:45–52PubMedCrossRefGoogle Scholar
  74. 74.
    Nadler JV, Perry BW, Cotman CW (1978) Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 271:676–677PubMedCrossRefGoogle Scholar
  75. 75.
    Ben Ari Y, Lagowska J, Tremblay E, Le Gal LS (1979) A new model of focal status epilepticus: intra-amygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures. Brain Res 163:176–179PubMedCrossRefGoogle Scholar
  76. 76.
    Cavalheiro EA, Riche DA, Le Gal LS (1982) Long-term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol 53:581–589PubMedCrossRefGoogle Scholar
  77. 77.
    Riban V, Bouilleret V, Pham L, Fritschy JM, Marescaux C, Depaulis A (2002) Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience 112:101–111PubMedCrossRefGoogle Scholar
  78. 78.
    Klein S, Bankstahl M, Löscher W (2015) Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice. Neuropharmacology 90:53–62PubMedCrossRefGoogle Scholar
  79. 79.
    Duveau V, Pouyatos B, Bressand K, Bouyssieres C, Chabrol T, Roche Y, Depaulis A, Roucard C (2016) Differential effects of antiepileptic drugs on focal seizures in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. CNS Neurosci Ther 22:497–506PubMedCrossRefGoogle Scholar
  80. 80.
    Guillemain I, Kahane P, Depaulis A (2012) Animal models to study aetiopathology of epilepsy: what are the features to model? Epileptic Disord 14:217–225PubMedGoogle Scholar
  81. 81.
    Klee R, Brandt C, Töllner K, Löscher W (2017) Various modifications of the intrahippocampal kainate model of mesial temporal lobe epilepsy in rats fail to resolve the marked rat-to-mouse differences in type and frequency of spontaneous seizures in this model. Epilepsy Behav 68:129–140PubMedCrossRefGoogle Scholar
  82. 82.
    Grabenstatter HL, Ferraro DJ, Williams PA, Chapman PL, Dudek FE (2005) Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy. Epilepsia 46:8–14PubMedCrossRefGoogle Scholar
  83. 83.
    Grabenstatter HL, Clark S, Dudek FE (2007) Anticonvulsant effects of carbamazepine on spontaneous seizures in rats with kainate-induced epilepsy: comparison of intraperitoneal injections with drug-in-food protocols. Epilepsia 48:2287–2295PubMedGoogle Scholar
  84. 84.
    Grabenstatter HL, Dudek FE (2008) A new potential AED, carisbamate, substantially reduces spontaneous motor seizures in rats with kainate-induced epilepsy. Epilepsia 49:1787–1794PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Ali A, Dua Y, Constance JE, Franklin MR, Dudek FE (2012) A once-per-day, drug-in-food protocol for prolonged administration of antiepileptic drugs in animal models. Epilepsia 53:199–206PubMedCrossRefGoogle Scholar
  86. 86.
    Thomson K, West P, Newell T, Metcalf C, Wilcox K (2016) Rapid screening for antiseizure therapies utilizing repeated dosing in chronically epileptic rats. American Epilepsy Society 70th annual meeting abstracts online abst. 3.224.Google Scholar
  87. 87.
    Löscher W (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 20:359–368PubMedCrossRefGoogle Scholar
  88. 88.
    West P, Saunders G, Billingsley P, Smith M, Metcalf C, White H, Wilcox K (2016) Spontaneous electrographic bursting in the medial entorhinal cortex of kainate-lesioned rats is refractory to multiple classes of anti-seizure drugs. American Epilepsy Society 70th annual meeting abstracts online abst. 3.061.Google Scholar
  89. 89.
    Curia G, Longo D, Biagini G, Jones RS, Avoli M (2008) The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods 172:143–157PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    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 9:315–335PubMedCrossRefGoogle Scholar
  91. 91.
    Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA (1989) Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: A novel model of intractable epilepsy. Synapse 3:154–171PubMedCrossRefGoogle Scholar
  92. 92.
    Cavalheiro EA, Leite JP, Bortolotto 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 32:778–782PubMedCrossRefGoogle Scholar
  93. 93.
    Leite JP, Cavalheiro EA (1995) Effects of conventional antiepileptic drugs in a model of spontaneous recurrent seizures in rats. Epilepsy Res 20:93–104PubMedCrossRefGoogle Scholar
  94. 94.
    Glien M, Brandt C, Potschka H, Löscher W (2002) Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy. Epilepsia 43:350–357PubMedCrossRefGoogle Scholar
  95. 95.
    Bankstahl M, Bankstahl JP, Löscher W (2012) Inter-individual variation in the anticonvulsant effect of phenobarbital in the pilocarpine rat model of temporal lobe epilepsy. Exp Neurol 234:70–84PubMedCrossRefGoogle Scholar
  96. 96.
    Mazarati AM, Thompson KW, Suchomelova L, Sankar R, Shirasaka Y, Nissinen J, Pitkänen A, Bertram E, Wasterlain C (2006) Status epilepticus: electrical stimulation models. In: Pitkänen M, Schwartzkroin PA, Moshé SL (eds.) Models of seizures and epilepsy. Elsevier, Amsterdam, pp 449–464CrossRefGoogle Scholar
  97. 97.
    Brandt C, Volk HA, Löscher W (2004) Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Epilepsia 45:1488–1497PubMedCrossRefGoogle Scholar
  98. 98.
    Bethmann K, Brandt C, Löscher W (2007) Resistance to phenobarbital extends to phenytoin in a rat model of temporal lobe epilepsy. Epilepsia 48:816–826PubMedCrossRefGoogle Scholar
  99. 99.
    Stables JP, Bertram E, Dudek FE, Holmes G, Mathern G, Pitkänen A, White HS (2003) Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the NIH/NINDS/AES models II workshop. Epilepsia 44:1472–1478PubMedCrossRefGoogle Scholar
  100. 100.
    Brandt C, Bethmann K, Gastens AM, Löscher W (2006) The multidrug transporter hypothesis of drug resistance in epilepsy: proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis 24:202–211PubMedCrossRefGoogle Scholar
  101. 101.
    Feldmann M, Asselin MC, Liu J, Wang S, McMahon A, Anton-Rodriguez J, Walker M, Symms M, Brown G, Hinz R, Matthews J, Bauer M, Langer O, Thom M, Jones T, Vollmar C, Duncan JS, Sisodiya SM, Koepp MJ (2013) P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study. Lancet Neurol 12:777–785PubMedCrossRefGoogle Scholar
  102. 102.
    Blanco MM, Dos SJ Jr, Perez-Mendes, P., Kohek SR, Cavarsan CF, Hummel M, Albuquerque C, Mello LE (2009) Assessment of seizure susceptibility in pilocarpine epileptic and nonepileptic Wistar rats and of seizure reinduction with pentylenetetrazole and electroshock models. Epilepsia 50:824–831PubMedCrossRefGoogle Scholar
  103. 103.
    Töllner K, Twele F, Löscher W (2016) Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures. Epilepsy Behav 57:95–104PubMedCrossRefGoogle Scholar
  104. 104.
    Bankstahl M, Bankstahl JP, Löscher W (2013) Pilocarpine-induced epilepsy in mice alters seizure thresholds and the efficacy of antiepileptic drugs in the 6-Hz psychomotor seizure model. Epilepsy Res 107:205–216PubMedCrossRefGoogle Scholar
  105. 105.
    Leclercq K, Kaminski RM (2015) Status epilepticus induction has prolonged effects on the efficacy of antiepileptic drugs in the 6-Hz seizure model. Epilepsy Behav 49:55–60PubMedCrossRefGoogle Scholar
  106. 106.
    Erker T, Brandt C, Töllner K, Schreppel P, Twele F, Schidlitzki A, Löscher W (2016) The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice. Epilepsia 57:698–705PubMedCrossRefGoogle Scholar
  107. 107.
    Löscher W (2017) The search for new screening models of pharmacoresistant epilepsy: is induction of acute seizures in epileptic rodents a suitable approach? Neurochem Res (in press)Google Scholar
  108. 108.
    Annegers JF, Rocca WA, Hauser WA (1996) Causes of epilepsy: contributions of the Rochester epidemiology project. Mayo Clin Proc 71:570–575PubMedCrossRefGoogle Scholar
  109. 109.
    Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, Cavalcanti D, Baulac M (1998) Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 51:1256–1262PubMedCrossRefGoogle Scholar
  110. 110.
    Stephen LJ, Kwan P, Brodie MJ (2001) Does the cause of localisation-related epilepsy influence the response to antiepileptic drug treatment? Epilepsia 42:357–362PubMedCrossRefGoogle Scholar
  111. 111.
    Mohanraj R, Brodie MJ (2005) Outcomes in newly diagnosed localization-related epilepsies. Seizure 14:318–323PubMedCrossRefGoogle Scholar
  112. 112.
    Pitkänen A, Kharatishvili I, Karhunen H, Lukasiuk K, Immonen R, Nairismagi J, Grohn O, Nissinen J (2007) Epileptogenesis in experimental models. Epilepsia 48(Suppl 2):13–20PubMedCrossRefGoogle Scholar
  113. 113.
    Pitkänen A, Bolkvadze T, Immonen R (2011) Anti-epileptogenesis in rodent post-traumatic epilepsy models. Neurosci Lett 497:163–171PubMedCrossRefGoogle Scholar
  114. 114.
    Eastman CL, Verley DR, Fender JS, Temkin NR, D’Ambrosio R (2010) ECoG studies of valproate, carbamazepine and halothane in frontal-lobe epilepsy induced by head injury in the rat. Exp Neurol 224:369–388PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Eastman CL, Verley DR, Fender JS, Stewart TH, Nov E, Curia G, D’Ambrosio R (2011) Antiepileptic and antiepileptogenic performance of carisbamate after head injury in the rat: blind and randomized studies. J Pharmacol Exp Ther 336:779–790PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Libbey JE, Fujinami RS (2011) Neurotropic viral infections leading to epilepsy: focus on Theiler’s murine encephalomyelitis virus. Future Virol 6:1339–1350PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Wilcox K, Vanagas F, Underwood T, Patel D, Metcalf C (2016) Evaluation of prototype antiseizure drugs in the theiler’s murine encephalomyelitis virus-induced model of temporal lobe epilepsy. American Epilepsy Society 70th annual meeting abstracts online abst. 1.259Google Scholar
  118. 118.
    Bender RA, Baram TZ (2007) Epileptogenesis in the developing brain: what can we learn from animal models? Epilepsia 48(Suppl 5):2–6PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Wasterlain CG, Gloss DS, Niquet J, Wasterlain AS (2013) Epileptogenesis in the developing brain. Handb Clin Neurol 111:427–439PubMedCrossRefGoogle Scholar
  120. 120.
    Auvin S, Pineda E, Shin D, Gressens P, Mazarati A (2012) Novel animal models of pediatric epilepsy. Neurotherapeutics 9:245–261PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Kandratavicius L, Balista PA, Lopes-Aguiar C, Ruggiero RN, Umeoka EH, Garcia-Cairasco N, Bueno-Junior LS, Leite JP (2014) Animal models of epilepsy: use and limitations. Neuropsychiatr Dis Treat 10:1693–1705PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Galanopoulou AS, Moshe SL (2015) Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: a view from preclinical studies. Neurobiol Dis 79:135–149PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Löscher W (1984) Genetic animal models of epilepsy as a unique resource for the evaluation of anticonvulsant drugs. A review. Methods Findings Experiment. Clin Pharmacol 6:531–547Google Scholar
  124. 124.
    Vergnes M, Marescaux C, Micheletti G, Reis J, Depaulis A, Rumbach L, Warter JM (1982) Spontaneous paroxysmal electroclinical patterns in rat: a model of generalized non-convulsive epilepsy. Neurosci Lett 33:97–101PubMedCrossRefGoogle Scholar
  125. 125.
    Depaulis A, David O, Charpier S (2016) The genetic absence epilepsy rat from Strasbourg as a model to decipher the neuronal and network mechanisms of generalized idiopathic epilepsies. J Neurosci Methods 260:159–174PubMedCrossRefGoogle Scholar
  126. 126.
    Van Luijtelaar G, Zobeiri M (2014) Progress and outlooks in a genetic absence epilepsy model (WAG/Rij). Curr Med Chem 21:704–721PubMedCrossRefGoogle Scholar
  127. 127.
    Guerrini R, Marini C, Mantegazza M (2014) Genetic epilepsy syndromes without structural brain abnormalities: clinical features and experimental models. Neurother 11:269–285CrossRefGoogle Scholar
  128. 128.
    Blumenfeld H, Klein JP, Schridde U, Vestal M, Rice T, Khera DS, Bashyal C, Giblin K, Paul-Laughinghouse C, Wang F, Phadke A, Mission J, Agarwal RK, Englot DJ, Motelow J, Nersesyan H, Waxman SG, Levin AR (2008) Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 49:400–409PubMedCrossRefGoogle Scholar
  129. 129.
    Russo E, Citraro R, Scicchitano F, De Fazio S, Di Paola ED, Constanti A, De Sarro G (2010) Comparison of the antiepileptogenic effects of an early long-term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy. Epilepsia 51:1560–1569PubMedCrossRefGoogle Scholar
  130. 130.
    Russo E, Citraro R, Scicchitano F, De Fazio S, Perrotta I, Di Paola ED, Constanti A, De Sarro G (2011) Effects of early long-term treatment with antiepileptic drugs on development of seizures and depressive-like behavior in a rat genetic absence epilepsy model. Epilepsia 52:1341–1350PubMedCrossRefGoogle Scholar
  131. 131.
    Dezsi G, Ozturk E, Stanic D, Powell KL, Blumenfeld H, O’Brien TJ, Jones NC (2013) Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia 54:635–643PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC (2017) Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain 140:669–683PubMedGoogle Scholar
  133. 133.
    Denayer T, Stöhr T, van Roy M (2014) Animal models in translational medicine: validation and prediction. New Hor Transl Med 2:5–11Google Scholar
  134. 134.
    Wartha K, Herting F, Hasmann M (2014) Fit-for purpose use of mouse models to improve predictivity of cancer therapeutics evaluation. Pharmacol Ther 142:351–361PubMedCrossRefGoogle Scholar
  135. 135.
    Willner P, Belzung C (2015) Treatment-resistant depression: are animal models of depression fit for purpose? Psychopharmacology 232:3473–3495PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Pharmacology, Toxicology and PharmacyUniversity of Veterinary MedicineHanoverGermany
  2. 2.Center for Systems NeuroscienceHanoverGermany

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