Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Key factors in the discovery and development of new antiepileptic drugs

Key Points

  • Most available AEDs have been found to exert their anticonvulsant action through a modulatory effect on voltage- and receptor-gated ion channels.

  • Genetic mouse models have been developed in recent years that recapitulate many of the features of human genetic epilepsy resulting from a specific defect in a particular receptor- or voltage-gated ion channel.

  • Transgenic mice are not widely used for AED discovery. However, that does not imply that they will not ultimately find a place in the routine evaluation of investigational AEDs.

  • Inflammatory cytokines such as interleukin-1β (IL-1β), tumour necrosis factor, and IL-6 can contribute to both acute neuronal excitability and chronic molecular changes that play a part in the development of epilepsy.

  • The successful characterization of the therapeutic potential of an AED has relied heavily on its profile in animal seizure and epilepsy models. Epilepsy, unlike many other central nervous system disorders, has benefited from predictive animal models that have been developed over the years.

  • Current models have failed to identify highly effective therapies for patients with pharmacoresistant epilepsy, which underscores the need for more predictive models of this form of epilepsy.

  • Although some AEDs in clinical development rely on novel mechanisms of action, many are second-generation molecules that circumvent the problems associated with first-generation compounds.

Abstract

Since the early 1990s, many new antiepileptic drugs (AEDs) that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug–drug interactions have entered the market. However, despite the therapeutic arsenal of old and new AEDs, approximately 30% of patients with epilepsy still suffer from seizures. Thus, there remains a substantial need for the development of more efficacious AEDs for patients with refractory seizures. Here, we briefly review the emerging knowledge on the pathological basis of epilepsy and how it might best be used in the design of new therapeutics. We also discuss the current approach to AED discovery and highlight some of the unique features of newer models of pharmacoresistance and epileptogenesis that have emerged in recent years.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Proposed mechanisms of action of currently available AEDs at excitatory and inhibitory synapses.
Figure 2: Metabolic pathways of the licarbazepine prodrugs eslicarbazepine acetate (ESL) and oxcarbazepine (OXC).
Figure 3: Structural requirements for valproic acid (VPA)-associated teratogenicity and hepatotoxicity.

Similar content being viewed by others

References

  1. Bialer, M. et al. Progress report on new antiepileptic drugs: a summary of the Eighth Eilat Conference (EILAT VIII). Epilepsy Res. 73, 1–52 (2007).

    Article  PubMed  Google Scholar 

  2. Bialer, M. et al. Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res. 83, 1–43 (2009). An extensive summary of the preclinical pharmacology and clinical development of anticonvulsant drugs in development.

    Article  PubMed  Google Scholar 

  3. Bialer, M. New antiepileptic drugs (AEDs) in clinical development which are second generation to existing AEDs. Expert Opin. Invest. Drug. 15, 637–647 (2006). This review shows that the second-generation approach is quite popular in the development of new AEDs.

    Article  CAS  Google Scholar 

  4. Callaghan, B. C., Anand, K., Hesdorffer, D., Hauser, W. A. & French, J. A. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann. Neurol. 62, 382–289 (2007).

    Article  PubMed  Google Scholar 

  5. Luciano, A. L. & Shorvon, S. D. Results of treatment changes in patientswith apparently drug-resistant chronic epilepsy. Ann. Neurol., 62, 375–381 (2007).

    Article  CAS  Google Scholar 

  6. White, H. S. et al. in Antiepileptic Drugs 5th edn (eds Levy, R. H., Mattson, R. H., Meldrum, B. S. & Perucca, E.) 36–48 (Lippincott Williams & Wilkins, New York, 2002).

    Google Scholar 

  7. Rogawski, M. A. Diverse mechanisms of antiepileptic drugs in development. Epilepsy Res. 69, 273–284 (2006). An excellent overview of the mechanisms of AEDs in development, emphasizing that most AEDs have multiple mechanisms of action.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Smith, M., Wilcox, K. S. & White, H. S. Discovery of antiepileptic drugs. Neurotherapeutics 4, 12–17 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rogawski, M. A. & Bazil, C. W. New molecular targets for antiepileptic drugs: α2δ, SBV2A, and Kv/KCNQ/M potassium channels. Curr. Neuro. Neurosci. Rep. 8, 345–352 (2008). An excellent overview of the diverse molecular mechanisms of three AEDs identified by screening in non-discriminating animal seizure and epilepsy models.

    Article  CAS  Google Scholar 

  10. Perucca, E., French, J. & Bialer, M. Developing novel antiepileptic drugs (AEDs): challenges, incentives and recent advances. Lancet Neurol. 6, 793–804 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Bialer, M., Twyman, R. E. & White, H. S. Correlation analysis between anticonvulsant ED50 values of antiepileptic drugs in mice and rats and their therapeutic doses and plasma levels. Epilepsy Behav. 5, 866–872 (2004).

    Article  PubMed  Google Scholar 

  12. Lynch, B. A. et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl Acad. Sci. USA 101, 9861–9866 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gillard, M. Chaterlain, P. & Fuks, B. Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein. Eur. J. Pharmacol. 24, 102–108 (2006).

    Article  CAS  Google Scholar 

  14. Kaminski, R. M. et al. SV2A protein is a broad-spectrum anticonvulsant agent: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 54, 715–720 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Roeloff, R. et al. In vivo profile of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide], a potent and selective KCNQ2/Q3 (Kv7.2/7.3) activator in rodent anticonvulsant models. J. Pharmacol. Exper. Ther. 326, 818–828 (2008).

    Article  CAS  Google Scholar 

  16. Yu, F. H. et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neurosci. 9, 1142–1149 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Vezzani, A., Balosso, S. & Ravizza, T. The role of cytokines in the pathophysiology of epilepsy. Brain Behav. Immun. 2, 797–803 (2008). A review of emerging evidence supporting a link between the release of inflammatory cytokines and the damage and network organization associated the development of epilepsy.

    Article  CAS  Google Scholar 

  18. Marcon, J. et al. Age-dependent vascular changes induced by status epilepticus in rat forebrain: implications for epileptogenesis. Neurobiol. Dis. 34, 121–132 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Ravizza, T. et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol. Dis. 29, 142–160 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Zibell, G. et al. Celecoxib prevents seizure-induced up-regulation of endothelial p-glycoprotein in the blood-brain-barrier. Abstract T158 (8th European Congress on Epileptology, Berlin, Germany, 2008).

  21. Pitkänen, A. & Sutula, T. P. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol. 1, 173–181 (2002).

    Article  PubMed  Google Scholar 

  22. Fabene, P. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nature Med. 14 1377–1383 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Kim, J. V., Kang, S. S., Dustin, M. L. & McGavern, D. B. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457, 191–195 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Ransohoff, R. M. Barrier to electrical storms. Nature 457 155–156 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Medhi, B. et al. Experimentally induced various inflammatory models and seizure: understanding the role of cytokine in rat. Abstract E494 (8th European Congress on Epileptology, Berlin, Germany, 2008).

  26. Rao, R. S. et al. Experimentally induced various inflammatory models and seizure: understanding the role of cytokine in rat. Eur. Neuropsychopharmacol. 18, 760–767 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Manent, J. B., Wang, Y., Chang, Y., Paramasivam, M. & LoTurco, J. J. Dcx reexpression reduces subcortical band heterotopia and seizure threshold in an animal model of neuronal migration disorder. Nature Med. 15, 84–90 (2009). An innovative non-pharmacological approach to seizure treatment involving re-engagement of developmental programmes to enhance neuronal migration and reduce the size of subcortical band heterotopia and seizure susceptibility.

    Article  CAS  PubMed  Google Scholar 

  28. Alvarez-Dolado, M. et al. Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain. J. Neurosci. 26, 7380–7389 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Baraban, S. C. et al. Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice. Proc. Natl Acad. Sci. USA 106, 15472–15477 (2009). This study suggests that a cell-grafting strategy could be used to treat complex neurological disorders such as epilepsy. It provides proof of concept for the use of embryonic stem cell implants to enhance inhibitory neurotransmission.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bialer, M. & Yagen, B. Valproic acid — second generation. Neurotherapeutics 4, 130–137 (2007). A comprehensive review of all second-generation drugs to VPA with potential CNS activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. White, H. S. et al. The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models. Epilepsia 49, 1213–1220 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Perucca, E., Cloyd, J., Critchley, D. & Fuseau, E. Rufinamide: clinical pharmacokinetics and concentration — response relationships in patients with epilepsy. Epilepsia 49, 1123–1141 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Wu, C. Y. & Bennet, L. Z. Predicting drug disposition via application of BCS: transport/absorption elimination interplay and development of biopharmaceutics drug disposition classification system. Pharm. Res. 22, 11–23 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Otto, J. F., Kimbal, M. M. & Wilcox, K. S. Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission. Mol. Pharmacol. 61, 921–927 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Rigdon, G. ICA-105665. Antiepileptic Drug Trials X, Syllabus (Coral Gables, Florida, 15–17 Apr 2009).

    Google Scholar 

  36. Squillacote, F. Perampanel (E2007). Antiepileptic Drug Trials X, Syllabus (Coral Gables, Florida, 15–17 Apr 2009).

    Google Scholar 

  37. Howes, J. F. & Bell, C. B. Talampanel. Neurotherapeutics 4, 126–129 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rogawski, M. A., Kurzman, R. S., Yamaguhci, S. I. & Li, H. Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse. Neuropharmacology 40, 28–35 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Gottwald, M. F. & Aminoff, M. J. New frontiers in the pharmacological management of Parkinson's. Drug. Today 44, 531–545 (2008).

    Article  CAS  Google Scholar 

  40. Eisai Press Release. Status of the E2007 (perampanel) development program — termination of Parkinson's disease clinical development and focus on neuropathic pain and epilepsy indications. Eisai website [online] (2008).

  41. Bialer, M. et al. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res. 61, 1–48 (2004).

    Article  PubMed  Google Scholar 

  42. Traynor, B. J. et al. Neuroprotective agents in clinical trials in ALS: a systematic assessment. Neurology 67, 20–27 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Aujla, P. K., Fettell, M. R. & Jaensen, F. Talampanel suppresses the acute and chronic effects of seizures in a rodent neonatal seizure model. Epilepsia 50 694–701 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Beguin, C., LeTrain, A., Stables, J. P., Voyksner, R. D. & Kohn, H. N-substituted amino acid N-benzylamides: synthesis, anticonvulsant and metabolic activities. Bioorg. Chem. 12, 3079–3096 (2004).

    Article  CAS  Google Scholar 

  45. Stoehr, T. et al. Lacosamide, a novel anticonvulsant drug, shows efficacy with wide safety margin in rodent models for epilepsy. Epilepsy Res. 74, 147–154 (2007).

    Article  CAS  Google Scholar 

  46. Errington, A. C., Coyne, L., Stohr, T., Selve, N. & Lees, G. Seeking a mechanism of action for the novel anticonvulsant lacosamide. Neuropharmacology 50, 1016–1029 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Beyrueter, B. K. et al. Lacosamide: a review of preclinical properties. CNS Drug Rev. 13, 21–42 (2007).

    Article  Google Scholar 

  48. Czech, T. et al. Reduction of hippocampal collapsing response mediated protein-2 in patients with mesial temporal lobe epilepsy. Neurochem. Res. 28, 2189–2196 (2004).

    Article  Google Scholar 

  49. Perucca, E., Yasothan, U., Clincke, G. & Kirkpatrick, P. Lacosamide. Nature Rev. Drug Discov. 7, 973–974 (2008).

    Article  CAS  Google Scholar 

  50. Shaibani, A., Biton, V., Rauck, R., Koch, B. & Simpson, J. Long term oral lacosamide in a painful diabetic neuropathy: a two-year open-label extension trial. Eur. J. Pain 13, 458–463 (2008).

    Article  PubMed  CAS  Google Scholar 

  51. White, H. S. et al. The novel investigational neuromodulator RWJ-333369 displays a broad-spectrum anticonvulsant profile in rodent seizure and epilepsy models. Epilepsia Abstr. 37, 320 (2006).

    Google Scholar 

  52. Francois, J., Boehrer, A. & Nehlig, A. Effects of carisbamate (RWJ-333369) in two models of genetically determined generalized epilepsy, the GEARS and the audiogenic Wistar AS. Epilepsia 49, 393–399 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Grabenstatter, H. & Dudek, F. E. A new potential AED, carisbamate, substantially reduces spontaneous motor seizures in rats with kainite-induced epilepsy. Epilepsia 49, 1787–1794 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Deshpande, L. S., Nagarkatti, N., Sombati, S. & DeLorenzo, R. J. The novel antiepileptic drug carisbamate (RWJ 333369) is effective in inhibiting spontaneous recurrent seizure discharges and blocking sustained repetitive firing in cultured hippocampal neurons. Epilepsy Res. 79, 158–165 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu, Y. et al. Carisbamate, a novel neuromodulator, inhibits voltage-gated, rat brain sodium channels. Epilepsy Res. 83, 66–72 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Whalley, B. J., Stephens, G. J. & Constanti, A. Investigation of the effects of the novel anticonvulsant compound carisbamate (RWJ-333369) on rat piriform cortical neurons in vitro. Br. J. Pharmacol. 156, 994–1008 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yao, C., Doose, D. R., Novak, G. & Bialer, M. Pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369, following single and multiple dosing to humans. Epilepsia 47, 1822–1829 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Sargentini-Maier, M. L. et al. The pharmacokinetics and CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral dose in healthy males. Br. J. Clin. Pharmacol. 63, 680–688 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sargentini-Maier, M. L., Espie, P., Coquette, A. & Stockis, A. Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy males. Drug Metab. Dispos. 26, 36–45 (2008).

    Article  CAS  Google Scholar 

  60. Rolan, P., Sargentini-Maier, M. L., Pigeolet, E. & Stockis, A. The pharmacokinetics & CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral dose in healthy men. Br. J. Clin. Pharmacol. 66, 71–75 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Margineanu, D. & Klitgaard, H. in Antiepileptic Drugs 5th edn (eds Levy, R. H., Mattson, R. H., Meldrum, B. S. & Perucca, E.) 419–427 (Lippincott Williams & Wilkins, New York, 2002).

    Google Scholar 

  62. Kenda, B. et al. Discovery of 4-substituted pyrrolidone butanamides as agents with significant antiepileptic activities. J. Med. Chem. 47, 530–549 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Volosov, A. et al. Enantioselective pharmacokinetics of 10-hydroxycarbazepine following oral administration of oxcarbazepine to healthy Chinese subjects. Clin. Pharmacol. Ther. 66, 547–553 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Bialer, M. in Antiepielptic Drugs 5th edn (eds Levy, R. H., Mattson, R. H., Meldrum, B. S. & Perucca, E.) 459–465 (Lippincott Williams & Wilkins, New York, 2002).

    Google Scholar 

  65. Elger, C., Halász, P., Maia, J., Almeida, L. & Soares-da-Silva, P. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia 50, 454–463 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Almeida, L., Bialer, M. & Soares- da-Silva, P. in Treatment of Epilepsy 3rd edn (eds Shorvon, S., Perucca, E. & Engel, J.) 485–498 (Wiley-Blackwell, Oxford, 2009).

    Book  Google Scholar 

  67. Souppart, C. et al. Pharmacokinetics of licarbazepine in healthy volunteers: single and multiple oral doses and effect of food. J. Clin. Pharmacol. 48, 563–569 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Tucker, G. T. Chiral switches. Lancet 355, 1085–1087 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Meador, K. J. et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N. Engl. J. Med. 360, 1597–1605 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Isoherranen, N. et al. Characterization of the anticonvulsant activity and pharmacokinetics of propylisopropyl acetamide and its enantiomers. Br. J. Pharmacol. 138, 602–613 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Isoherranen, N. et al. Pharmacokinetic-pharmacodynamic relationships of (2S,3S)-valnoctamide and its stereoisomer (2R,3S)-valnoctamide in rodent models of epilepsy. Pharm. Res. 20, 1293–1301 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Winkler, I. et al. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model for neuropathic pain. Br. J. Pharmacol. 146, 198–208 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kaufmann, D. et al. Evaluation of enantioselective antiallodynic profile and pharmacokinetics of propylisopropylacetamide, a chiral isomer of valproic acid amide. Neuropharmacology 54, 699–707 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Applebaum, J., Gayduk, J., Agam, G., Bersudsky, Y. & Belmaker, R. H. Valnoctamide as valproate substitute with low teratogenic potential: double blind controlled clinical trial. Bipolar Disord. 7, 30 (2005).

    Google Scholar 

  75. Winkler, I. et al. Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model for neuropathic pain. Neuropharmacology 49, 1110–1120 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Sobol, E., Bialer, M. & Yagen, B. Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives. J. Med. Chem. 47, 4316–4326 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Shimshoni, J. et al. The effect of CNS-active valproic acid constitutional isomers, cyclopropyl analogues and amide derivatives on neuronal growth cone behavior. Mol. Pharmacol. 71, 884–892 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Vajda, F. I. et al. Critical relationship between sodium valproate dose and human teratogenicity; results of the Australian register of anti-epileptic drugs in pregnancy. J. Clin. Neurosci. 11, 854–858 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Meador, K. J. Effect of in utero antiepileptic drug exposure. Epilepsy Curr. 8, 144–147 (2008).

    Google Scholar 

  80. Cundy, K. C. et al. XP13512 [±1-([(α-isobutanoyloxyethoxy)carbonyl]aminoethyl)-1cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporter. J. Pharmacol. Exp. Ther. 31, 315–323 (2004).

    Article  CAS  Google Scholar 

  81. Cundy, K. C. et al. XP13512 [±1-([(α-isobutanoyloxyethoxy)carbonyl]aminoethyl)-1cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J. Pharmacol. Exp.Ther. 311, 324–333 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Cundy, K. C. et al. Clinical pharmacokinetics of XP13512 a novel transported prodrug of gabapentin prodrug. J. Clin. Pharmacol. 48, 1378–1388 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Foreman, M. et al. In vivo pharmacological effects of JZP-4, a novel anticonvulsant, in models of anticonvulsant, antimania and antidepressant activity. Phramacol. Biochem. Behav. 89, 523–534 (2008).

    Article  CAS  Google Scholar 

  84. White, H. S. & Smith, M. D. in Advanced Therapy in Epilepsy (eds Wheless, J. W., Willmore, L. J. & Brumback, R. A.) 226–232 (B. C. Decker, Hamilton, 2009).

    Google Scholar 

  85. Guerrini, R. et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 39, 508–512 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Kalume, F., Yu, F. H., Westenbroek, R. E., Scheuer, T. & Catterall, W. A. Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy. J. Neurosci. 27, 11065–11074 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Oakley, J. C., Kalume, F., Yu, F. H., Scheuer, T. & Catterall, W. A. Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy. Proc. Natl Acad. Sci. USA 106, 3994–3999 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Klitgaard, H., Matagne, A., Gobert, J. & Wülfert, E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur. J. Pharmacol. 353, 191–206 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Matagne, A. & Klitgaard, H. Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man. Epilepsy Res. 31, 59–71 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Gower, A. J., Hirsch, E., Boehrer, A., Noyer, M. & Marescaux, C. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy. Epilepsy Res. 22, 207–213 (1995).

    Article  CAS  PubMed  Google Scholar 

  91. Löscher, W. & Hönack, D. Profile of ucb L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. Eur. J. Pharmacol. 232, 147–158 (1993).

    Article  PubMed  Google Scholar 

  92. Gower, A. J., Noyer, M., Verloes, R., Gobert, J. & Wülfert, E. ucb L059, a novel anti-convulsant drug: pharmacological profile in animals. Eur. J. Pharmacol. 222, 193–203 (1992).

    Article  CAS  PubMed  Google Scholar 

  93. Lothman, E. W., Salerno, R. A., Perlin, J. B. & Kaiser, D. L. Screening and characterization of antiepileptic drugs with rapidly hippocampal seizures in rats. Epilepsy Res. 2, 367–379 (1988).

    Article  CAS  PubMed  Google Scholar 

  94. Löscher, W. in Models of Seizures and Epilepsy (eds Pitkanen, A., Schwartzkroin, P. A. & Moshe, S. L.) 551–567 (Elsevier, New York, 2006).

    Book  Google Scholar 

  95. Loscher, W., Rundfeldt, C. & Honack, D. Pharmacological characterization of phenytoin-resistant amygdala-kindled rats, a new model of drug-resistant partial epilepsy. Epilepsy Res. 15, 207–219 (1993).

    Article  CAS  PubMed  Google Scholar 

  96. Rundfeldt, C. & Loscher, W. Anticonvulsant efficacy and adverse effects of phenytoin during chronic treatment in amygdala-kindled rats. J. Pharmacol. Exp. Ther. 266, 216–223 (1993).

    CAS  PubMed  Google Scholar 

  97. Postma, T., Krupp, E., Li, X. L., Post, R. M. & Weiss, S. R. Lamotrigine treatment during amygdala-kindled seizure development fails to inhibit seizures and diminishes subsequent anticonvulsant efficacy. Epilepsia 41, 1514–1521 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Srivastava, A., Woodhead, J. H. & White, H. S. Effect of lamotrigine, carbamazepine and sodium valproate on lamotrigine-resistant kindled rats. Epilepsia 44 (Suppl. 9), 42 (2003).

    Google Scholar 

  99. Srivastava, A., Franklin, M. R., Palmer, B. S. & White, H. S. Carbamazepine, but not valproate, displays pharmaco-resistance in lamotrigine-resistant amygdala kindled rats. Epilepsia 45 (Suppl. 7), 12 (2004).

    Google Scholar 

  100. Srivastava, A. & White, H. S. Retigabine decreases behavioral and electrographic seizures in the lamotrigine-resistant amygdala kindled rat model of pharmacoresistant epilepsy. Epilepsia 46 (Suppl. 8), 217–218 (2005).

    Google Scholar 

  101. Barton, M. E., Klein, B. D., Wolf, H. H. & White, H. S. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 47, 217–227 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Brandt, C., Volk, H. A. & Loscher, W. Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Epilepsia 45, 1488–1497 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Glien, M., Brandt, C., Potschka, H. & Loscher, W. Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy. Epilepsia 43, 350–357 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Leite, J. P. & Cavalheiro, E. A. Effects of conventional antiepileptic drugs in a model of spontaneous recurrent seizures in rats. Epilepsy Res. 20, 93–104 (1995).

    Article  CAS  PubMed  Google Scholar 

  105. Grabenstatter, H. L. & Dudek, F. E. The effect of carbamazepine on spontaneous seizures in freely-behaving rats with kainate-induced epilepsy. Epilepsia 46 (Suppl. 8), 287 (2005).

    Google Scholar 

  106. Grabenstatter, H. L., Ferraro, D. J., Williams, P. A., Chapman, P. L. & Dudek, F. E. 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, 8–14 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. van Vliet, E. A. et al. Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats. Epilepsia 47, 672–680 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Smyth, M. D., Barbaro, N. M. & Baraban, S. C. Effects of antiepileptic drugs on induced epileptiform activity in a rat model of dysplasia. Epilepsy Res. 50, 251–264 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Rho, J. M. & Sankar, R. The pharmacologic basis of antiepileptic drug action. Epilepsia 40, 1471–1483 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Ogiwara, I. et al. NaV1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J. Neurosci. 27, 5903–5914 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Davis, T. H., Chen, C. & Isom, L. L. Sodium channel β1 subunit neurite outgrowth in cerebellar granule neurons. J. Biol. Chem. 279, 51424–51432 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Planells-Cases, R. et al. Neuronal death and perinatal lethality in voltage-gated sodium channel alpha(II)-deficient mice. Biophys. J. 78, 2878–2891 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kearney, J. A. et al. A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience 102, 307–317 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Aptel, H. et al. The Cav3.2/α1H T-type Ca2+ current is a molecular determinant of excitatory effects of GABA in adult sensory neurons. Mol. Cell Neurosci. 36, 293–303 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Escayg, A., Jones, J. M., Kearney, J. A., Hitchcock, P. F. & Meisler, M. H. Calcium channel β4 (CACNB4): human ortholog of the mouse epilepsy gene lethargic. Genomics 50, 14–22 (1998).

    Article  CAS  PubMed  Google Scholar 

  116. Burgess, D. L. & Noebels, J. L. Single gene defects in mice: the role of voltage-dependent calcium channels in absence models. Epilepsy Res. 36, 111–122 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Watanabe, H. et al. Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. J. Neurochem. 75, 28–33 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Yang, Y. et al. Spontaneous deletion of epilepsy gene orthologs in a mutant mouse with a low electroconvulsive threshold. Hum. Mol. Genet. 12, 975–984 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Singh, N. A. et al. Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization. J. Physiol. 586, 3405–3423 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Smart, S. L. et al. Deletion of the KV1.1 potassium channel causes epilepsy in mice. Neuron 20, 809–819 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Guo, W. et al. Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction. Circ. Res. 97, 1342–1350 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Sur, C. et al. Loss of the major GABAA receptor subtype in the brain is not lethal in mice. J. Neurosci. 21, 3409–3418 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Vicini, S. et al. GABAA receptor α1 subunit deletion prevents developmental changes of inhibitory synaptic currents in cerebellar neurons. J. Neurosci. 21, 3009–3016 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tan, H. O. et al. Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proc. Natl Acad. Sci. USA 104, 17536–17541 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Manfredi, I. et al. Expression of mutant β2 nicotinic receptors during development is crucial for epileptogenesis. Hum. Mol. Genet. 18, 1075–1088 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Wong, J. Y. et al. Proconvulsant-induced seizures in α4 nicotinic acetylcholine receptor subunit knockout mice. Neuropharmacology 43, 55–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Klaassen, A. et al. Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy. Proc. Natl Acad. Sci USA 103, 19152–19157 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Teper, Y. et al. Nicotine-induced dystonic arousal complex in a mouse line harboring a human autosomal-dominant nocturnal frontal lobe epilepsy mutation. J. Neurosci. 27, 10128–10142 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Bersudsky, Y. et al. Valnoctamide as a valproate substitute with low teratogenic potential in mania: double-blind controlled clinical trial. Bipolar Disord. (in the press).

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Meir Bialer.

Ethics declarations

Competing interests

H.S.W. is a scientific co-founder of NeuroAdjuvants, a biotechnology company based in Salt Lake City that is focused on the development of metabolically stable, blood–brain barrier-penetrant neuropeptides for the treatment of neurological disorders and pain.

Related links

Related links

DATABASES

OMIM

severe myoclonic epilepsy of infancy

FURTHER INFORMATION

H. Steve White's homepage

Valnoctamide in Mania

Glossary

Pharmacoresistant epilepsy

A seizure disorder characterized by poor seizure control with currently available anticonvulsant drugs.

α2δ

An auxillary subunit of a voltage-gated Ca2+ channel and molecular target for the anticonvulsant drugs gabapentin, pregabalin and XP13512.

Audiogenic seizure

A generalized seizure induced by a sound stimulus, characterized by 'popcorn jumping', wild running and tonic limb extension. Frings and DBA/2J mice show genetic susceptibility to audiogenic seizures.

Tonic–clonic seizure

A generalized clinical seizure characterized by tonic limb extension followed by clonic jerking.

Spike–wave seizure

A generalized electrographic seizure that is characterized by an initial excitatory spike and subsequent inhibitory wave and is the hallmark feature of human generalized absence epilepsy. It is also a characteristic of several genetic animal models of absence seizures including the GAERS and Lethargic mouse.

Lethargic-mouse model

A genetic mouse model of spike–wave seizures that has a mutation in a voltage-gated Ca2+ channel subunit and a pharmacological profile consistent with human absence epilepsy.

Pentylenetetrazol

A compound that, when administered systemically to rodents, produces a characteristic generalized minimal clonic seizure featuring vibrissae twitching, jaw chomping, and forelimb clonus mediated by forebrain structures.

Lennox–Gastaut syndrome

A form of childhood-onset epilepsy that is difficult to treat and often presents between the second and sixth year of life. It is characterized by frequent seizures that are often mixed in type and is often accompanied by mental retardation and behaviour problems.

Maximal electroshock seizure

(MES). A brainstem seizure that was first used in 1937 to identify the anticonvulsant potential of phenytoin. Since then, it has been a primary model for the initial identification of anticonvulsant activity.

Kindled seizures

The induction of seizures by repeated delivery of subconvulsive electrical stimuli to a limbic brain structure. The kindling model is routinely used in the search for new therapies for partial epilepsy.

6 Hz psychomotor seizure model

A limbic seizure model that is activated by a low frequency (6 Hz) corneal stimulation and characterized by a stun, vibrissae chomping, forelimb clonus and Straub tail.

Genetic absence epileptic rat of Strasbourg

A genetic rat model that displays characteristic 6–7 Hz spike–wave electrographic seizures and a pharmacological profile consistent with generalized absence epilepsy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bialer, M., White, H. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9, 68–82 (2010). https://doi.org/10.1038/nrd2997

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2997

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing