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:

The neurobiology of antiepileptic drugs

Nature Reviews Neuroscience volume 5, pages 553–564 (2004)Cite this article

Key Points

  • Antiepileptic drugs (AEDs) protect against seizures by modulation of voltage-gated sodium and calcium channels, enhancement of GABAA (γ-aminobutyric acid, type A) receptor-mediated synaptic inhibition, and inhibition of ionotropic glutamate receptor-mediated synaptic excitation.

  • Sodium channel-blocking AEDs, including phenytoin, carbamazepine and lamotrigine, inhibit high-frequency repetitive spike firing during the spread of seizure activity without affecting ordinary ongoing neural activity. These drugs bind preferentially to depolarized sodium channels and induce a non-conducting state that is similar to channel inactivation, but from which recovery is much slower, allowing the block to accumulate during repetitive activation of the channel, as occurs with epileptic bursting. In addition, the drug binds slowly so that there is preferential block of firing during sustained epileptic depolarizations.

  • Persistent or non-inactivating sodium current represents only a fraction of the sodium current, but might contribute to the initiation and maintenance of epileptiform activity. Preferential inhibition of persistent sodium current probably contributes to the protective activity of phenytoin and possibly other sodium channel blocking AEDs.

  • Gabapentin binds with high affinity to the auxiliary calcium channel subunits α2δ-1 and α2δ-2. The functional consequences of this interaction are not fully defined, but recent studies indicate that gabapentin might inhibit calcium currents, resulting in reduced excitatory neurotransmission.

  • In the thalamus, T-type calcium channels are essential for the abnormal oscillatory behaviour that underlies generalized absence seizures. Ethosuximide inhibits these channels, accounting for its anti-absence activity.

  • Inhibitory GABAA receptor-mediated synaptic interactions are important in restraining the natural tendency of brain circuits in regions that are susceptible to epileptic activity (including the neocortex, hippocampus and amygdala) to undergo the transition into synchronized epileptiform activity. Many AEDs enhance GABAA receptor inhibition either through positive modulatory interactions with GABAA receptors (benzodiazepines, barbiturates, felbamate and topiramate) or by modifying the dynamics of GABA-mediated inhibitory synaptic function, as is the case for vigabatrin, an irreversible suicide inhibitor of the GABA degradative enzyme GABA transaminase, and tiagabine, an inhibitor of the high-affinity GABA transporter GAT1.

  • Several marketed AEDs might act partly by inhibition of ionotropic glutamate receptors, including felbamate, which inhibits NMDA (N-methyl-D-aspartate) receptors, and topiramate, which inhibits kainate receptors.

  • There is remarkable overlap between the ion channel targets of AEDs and human epilepsy genes, illustrating the pivotal importance of ion channels in epilepsy. In many cases, the AEDs and mutations induce functionally opposite effects on channel behaviour. So, whereas the mutations lead to increased seizure susceptibility through gain-of-function effects on voltage-gated sodium and calcium channel gating or reduced efficacy of GABAA receptors or potassium channels, AEDs inhibit sodium or calcium channels, or enhance the activity of GABAA receptors or potassium channels.

Abstract

Antiepileptic drugs (AEDs) provide satisfactory control of seizures for most patients with epilepsy. The drugs have the remarkable ability to protect against seizures while permitting normal functioning of the nervous system. AEDs act on diverse molecular targets to selectively modify the excitability of neurons so that seizure-related firing is blocked without disturbing non-epileptic activity. This occurs largely through effects on voltage-gated sodium and calcium channels, or by promoting inhibition mediated by GABAA (γ-aminobutyric acid, type A) receptors. The subtle biophysical modifications in channel behaviour that are induced by AEDs are often functionally opposite to defects in channel properties that are caused by mutations associated with epilepsy in humans.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Lamotrigine selectively blocks epileptiform discharges without affecting ordinary action potential firing.
Figure 2: Antiepileptic drugs (AEDs) and sodium channels.
Figure 3: Stick and space-filling views showing diphenyl moiety common to the sodium-channel-blocking antiepileptic drugs phenytoin, lamotrigine and carbamazepine.
Figure 4: GABA receptors and antiepileptic drugs.

Similar content being viewed by others

References

  1. Rogawski, M. A. & Löscher, W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nature Med. 10, 685–692 (2004).A review of the actions of AEDs in conditions other than epilepsy, focusing on disease-related ion channel plasticity and long-term effects on signalling pathways.

    Article  CAS  PubMed  Google Scholar 

  2. Tatulian, L., Delmas, P., Abogadie, F. C. & Brown, D. A. Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J. Neurosci. 21, 5535–5545 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Rogawski, M. A. in Neurotherapeutics: Emerging Strategies (eds Pullan, L. & Patel, J.) 193–273 (Humana, Totowa, New Jersey, 1996).

    Book  Google Scholar 

  4. Schmutz, M., Brugger, F., Gentsch, C., McLean, M. J. & Olpe, H. R. Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action. Epilepsia 35 (Suppl. 5), S47–50 (1994).

    Article  PubMed  Google Scholar 

  5. Ambrósio, A. F. et al. Inhibition of glutamate release by BIA 2-093 and BIA 2-024, two novel derivatives of carbamazepine, due to blockade of sodium but not calcium channels. Biochem. Pharmacol. 61, 1271–1275 (2001).

    Article  PubMed  Google Scholar 

  6. Schauf, C. L. Zonisamide enhances slow sodium inactivation in Myxicola. Brain Res. 413, 185–188 (1987).

    Article  CAS  PubMed  Google Scholar 

  7. Taglialatela, M., Ongini, E., Brown, A. M., Di Renzo, G. & Annunziato, L. Felbamate inhibits cloned voltage-dependent Na+ channels from human and rat brain. Eur. J. Pharmacol. 316, 373–377 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Taverna, S., Sancini, G., Mantegazza, M., Franceschetti, S. & Avanzini, G. Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant topiramate. J. Pharmacol. Exp. Ther. 288, 960–968 (1999).

    CAS  PubMed  Google Scholar 

  9. Van den Berg, R. J., Kok, P. & Voskuyl, R. A. Valproate and sodium currents in cultured hippocampal neurons. Exp. Brain. Res. 93, 279–287 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Albus, H. & Williamson, R. Electrophysiologic analysis of the actions of valproate on pyramidal neurons in the rat hippocampal slice. Epilepsia 39, 124–139 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Taverna, S., Mantegazza, M., Franceschetti, S. & Avanzini, G. Valproate selectively reduces the persistent fraction of Na+ current in neocortical neurons. Epilepsy Res. 32, 304–308 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Xie, X. et al. Electrophysiological and pharmacological properties of the human brain type IIA Na+ channel expressed in a stable mammalian cell line. Pflugers Arch. 441, 425–433 (2001). In this paper, studies using human brain type IIA voltage-gated sodium channels stably expressed in CHO cells showed voltage- and use-dependent block by phenytoin and lamotrigine, but not valproate and gabapentin.

    Article  CAS  PubMed  Google Scholar 

  13. Remy, S., Urban, B. W., Elger, C. E. & Beck, H. Anticonvulsant pharmacology of voltage-gated Na+ channels in hippocampal neurons of control and chronically epileptic rats. Eur. J. Neurosci. 17, 2648–2658 (2003).

    Article  PubMed  Google Scholar 

  14. Willow, M., Gonoi, T. & Catterall, W. A. Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol. Pharmacol. 27, 549–558 (1985).

    CAS  PubMed  Google Scholar 

  15. Matsuki, N., Quandt, F. N., Ten Eick, R. E. & Yeh, J. Z. Characterization of the block of sodium channels by phenytoin in mouse neuroblastoma cells. J. Pharmacol. Exp. Ther. 228, 523–530 (1984).

    CAS  PubMed  Google Scholar 

  16. Ragsdale, D. S., Scheuer, T. & Catterall, W. A. Frequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in mammalian cell line, by local anesthetic, antiarrhythmic, and anticonvulsant drugs. Mol. Pharmacol. 40, 756–765 (1991). Characterization of the actions of phenytoin and carbamazepine on recombinant rat brain sodium channels.

    CAS  PubMed  Google Scholar 

  17. Xie, X., Lancaster, B., Peakman, T. & Garthwaite, J. Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na+ channels and with native Na+ channels in rat hippocampal neurones. Pflügers Arch. 430, 437–446 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Leach, M. J., Marden, C. M. & Miller, A. A. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia 27, 490–497 (1986).

    Article  CAS  PubMed  Google Scholar 

  19. Prakriya, M. & Mennerick, S. Selective depression of low-release probability excitatory synapses by sodium channel blockers. Neuron 26, 671–682 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Goldin, A. L. Mechanisms of sodium channel inactivation. Curr. Opin. Neurobiol. 13, 284–290 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Fleidervish, I. A., Friedman, A. & Gutnick, M. J. Slow inactivation of Na+ current and slow cumulative spike adaptation in mouse and guinea-pig neocortical neurones in slices. J. Physiol. (Lond.) 493, 83–97 (1996).

    Article  CAS  Google Scholar 

  22. Quandt, F. N. Modification of slow inactivation of single sodium channels by phenytoin in neuroblastoma cells. Mol. Pharmacol. 34, 557–565 (1988). Analysis of phenytoin block of single sodium channels in membrane patches.

    CAS  PubMed  Google Scholar 

  23. Kuo, C. C. & Bean, B. P. Na+ channels must deactivate to recover from inactivation. Neuron 12, 819–829 (1994). A demonstration that phenytoin stabilizes sodium channels of hippocampal neurons in a non-conducting state, distinct from fast inactivation, from which recovery is slow and requires the channel to deactivate.

    Article  CAS  PubMed  Google Scholar 

  24. Spampanato, J., Escayg, A., Meisler, M. H. & Goldin, A. L. Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. J. Neurosci. 21, 7481–7490 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Alekov, A. K., Rahman, M. M., Mitrovic, N., Lehmann-Horn, F. & Lerche, H. Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man. Eur. J. Neurosci. 13, 2171–2176 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Spampanato, J., Aradi, I., Soltesz, I. & Goldin, A. L. Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus. J. Neurophysiol. 91, 2040–2050 (2004).

    Article  PubMed  Google Scholar 

  27. Vallarta, J. M., Bell, D. B. & Reichert, A. Progressive encephalopathy due to chronic hydantoin intoxication. Am. J. Dis. Child. 128, 27–34 (1974).

    CAS  PubMed  Google Scholar 

  28. Löscher, W., Cramer, S. & Ebert, U. Limbic epileptogenesis alters the anticonvulsant efficacy of phenytoin in Sprague-Dawley rats. Epilepsy Res. 31, 175–186 (1998).

    Article  PubMed  Google Scholar 

  29. Kuo, C. C. & Bean, B. P. Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons. Mol. Pharmacol. 46, 716–725 (1994). Phenytoin is found to bind tightly to the fast inactivated state of sodium channels but binding occurs slowly, a key characteristic enabling phenytoin to disrupt epileptic discharges with minimal effects on normal firing activity.

    CAS  PubMed  Google Scholar 

  30. Kuo, C. C. & Lu, L. Characterization of lamotrigine inhibition of Na+ channels in rat hippocampal neurones. Br. J. Pharmacol. 121, 1231–1238 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bazil, C. W. & Pedley, T. A. in Antiepileptic Drugs, 5th Edition (eds Levy, R. H., Mattson, R. H., Meldrum, B. S. & Perucca, E.) 22–35 (Lippincott Williams & Wilkins, Philadelphia, 2002).

    Google Scholar 

  32. Kuo, C. C. A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol. Pharmacol. 54, 712–721 (1998). Studies with mixtures of the main sodium channel-blocking anticonvulsants demonstrate that these drugs bind to a similar recognition site on the inactivated conformation of the channel.

    CAS  PubMed  Google Scholar 

  33. Ragsdale, D. S., McPhee, J. C., Scheuer, T. & Catterall, W. A. Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. Proc. Natl Acad. Sci. USA 93, 9270–9275 (1996). Mutational analysis demonstrates the importance of F1764 and Y1771 in sodium channel transmembrane segment IVS6 in the binding of lidocaine and phenytoin.

    Article  CAS  PubMed  Google Scholar 

  34. Liu, G. et al. Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels. Neuropharmacology 44, 413–422 (2003). Site-directed mutagenesis reveals residues of the IVS6 transmembrane segment of the sodium channel that represent points of interaction for lamotrigine.

    Article  CAS  PubMed  Google Scholar 

  35. Yarov-Yarovoy, V. et al. Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na+ channel α-subunit. J. Biol. Chem. 276, 20–27 (2001). Site-directed mutagenesis reveals residues of the IIIS6 transmembrane segment of the sodium channel that represent points of interaction for lamotrigine and the local anesthetic etidocaine.

    Article  CAS  PubMed  Google Scholar 

  36. McPhee, J. C., Ragsdale, D. S., Scheuer, T. & Catterall, W. A. A critical role for transmembrane segment IVS6 of the sodium channel α-subunit in fast inactivation. J. Biol. Chem. 270, 12025–12034 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Smith, M. R., Smith, R. D., Plummer, N. W., Meisler, M. H. & Goldin, A. L. Functional analysis of the mouse Scn8a sodium channel. J. Neurosci. 18, 6093–6102 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Taddese, A. & Bean, B. P. Subthreshold sodium current from rapidly inactivating sodium channels drives spontaneous firing of tuberomammillary neurons. Neuron 33, 587–600 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Maurice, N., Tkatch, T., Meisler, M., Sprunger, L. K. & Surmeier, D. J. D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and persistent sodium currents in prefrontal cortex pyramidal neurons. J. Neurosci. 21, 2268–2277 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Segal, M. M. & Douglas, A. F. Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin. J. Neurophysiol. 77, 3021–3034 (1977). This paper shows that the tetrodotoxin-sensitive, persistent sodium current that results from rare late openings of voltage-gated sodium channels is more sensitive to phenytoin than is the transient current. Such late openings are hypothesized to be important in initiating and continuing epileptiform activity.

    Article  Google Scholar 

  41. Chao, T. I. & Alzheimer, C. Effects of phenytoin on the persistent Na+ current of mammalian CNS neurones. Neuroreport 6, 1778–1780 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. Lampl, I., Schwindt, P. & Crill, W. Reduction of cortical pyramidal neuron excitability by the action of phenytoin on persistent Na+ current. J. Pharmacol. Exp. Ther. 284, 228–237 (1998).

    CAS  PubMed  Google Scholar 

  43. Niespodziany, I., Klitgaard, H. & Georg Margineanu, D. Is the persistent sodium current a specific target of anti-absence drugs? Neuroreport 15, 1049–1052 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Ketelaars, S. O., Gorter, J. A., van Vliet, E. A., Lopes da Silva, F. H. & Wadman, W. J. Sodium currents in isolated rat CA1 pyramidal and dentate granule neurones in the post-status epilepticus model of epilepsy. Neuroscience 105, 109–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Ellerkmann, R. K. et al. Molecular and functional changes in voltage-dependent Na+ channels following pilocarpine-induced status epilepticus in rat dentate granule cells. Neuroscience 119, 323–333 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Agrawal, N., Alonso, A. & Ragsdale, D. S. Increased persistent sodium currents in rat entorhinal cortex layer V neurons in a post-status epilepticus model of temporal lobe epilepsy. Epilepsia 44, 1601–1604 (2003).

    Article  PubMed  Google Scholar 

  47. Gastaldi, M., Robaglia-Schlupp, A., Massacrier, A., Planells, R. & Cau, P. mRNA coding for voltage-gated sodium channel β2 subunit in rat central nervous system: cellular distribution and changes following kainate-induced seizures. Neurosci. Lett. 249, 53–56 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Lossin, C., Wang, D. W., Rhodes, T. H., Vanoye, C. G. & George, A. L. Jr. Molecular basis of an inherited epilepsy. Neuron 34, 877–884 (2002). Recombinant human voltage-gated sodium channel SCN1A was coexpressed in cultured mammalian cells with human accessory subunits β1 and β2. GEFS+ mutations T875M, W1204R and R1648H in SCN1A were found to alter channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality is hypothesized to represent the biophysical mechanism that is responsible for the epileptic phenotype.

    Article  CAS  PubMed  Google Scholar 

  49. Catterall, W. A. Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol. 16, 521–555 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Turner, T. J. Calcium channels coupled to glutamate release. Prog. Brain. Res. 116, 3–14 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Gee, N. S. et al. The novel anticonvulsant drug, gabapentin (Neurontin) binds to the α2δ subunit of a calcium channel. J. Biol. Chem. 271, 5768–5776 (1996). A protein from guinea-pig cerebral cortex that binds [3H]gabapentin with high affinity is solubilized and purified; the partial N-terminal amino-acid sequence is identical to the calcium channel α 2 δ-subunit.

    Article  CAS  PubMed  Google Scholar 

  52. Marais, E., Klugbauer, N. & Hofmann, F. Calcium channel α2δ subunits — structure and gabapentin binding. Mol. Pharmacol. 59, 1243–1248 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Bryans, J. S. et al. Identification of novel ligands for the gabapentin binding site on the α2δ subunit of a calcium channel and their evaluation as anticonvulsant agents. J. Med. Chem. 4, 1838–1845 (1998).

    Article  Google Scholar 

  54. Dooley, D. J., Donovan, C. M., Meder, W. P. & Whetzel, S. Z. Preferential action of gabapentin and pregabalin at P/Q-type voltage-sensitive calcium channels: inhibition of K+-evoked [3H]-norepinephrine release from rat neocortical slices. Synapse 45, 171–190 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Dolphin, A. C. et al. The effect of α2δ and other accessory subunits on expression and properties of the calcium channel α1G. J. Physiol. (Lond.) 519, 35–45 (1999).

    Article  CAS  Google Scholar 

  56. Arikkath, J. & Campbell, K. P. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr. Opin. Neurobiol. 13, 298–307 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Brown, J. P. & Gee, N. S. Cloning and deletion mutagenesis of the α2δ calcium channel subunit from porcine cerebral cortex. J. Biol. Chem. 273, 25458–25465 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, M., Offord, J., Oxender, D. L. & Su, T. -Z. Structural requirement of the calcium channel subunit α2δ for gabapentin binding. Biochem. J. 342, 313–320 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Martin, D. J. et al. Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression. Neuropharmacology 42, 353–366 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Sutton, K. G., Martin, D. J., Pinnock, R. D., Lee, K. & Scott, R. H. Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones. Brit. J. Pharmacol. 135, 257–265 (2002).

    Article  CAS  Google Scholar 

  61. Sarantopoulos, C., McCallum, B., Kwok, W. M. & Hogan, Q. Gabapentin decreases membrane calcium currents in injured as well as in control mammalian primary afferent neurons. Reg. Anesth. Pain. Med. 27, 47–57 (2002).

    CAS  PubMed  Google Scholar 

  62. Dooley, D. J., Mieske, C. A. & Borosky, S. A. Inhibition of K+-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci. Lett. 280, 107–110 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Shimoyama, M., Shimoyama, N. & Hori, Y. Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn. Pain 85, 405–414 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Löscher, W., Honack, D. & Taylor, C. P. Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain. Neurosci. Lett. 128, 150–154 (1991).

    Article  PubMed  Google Scholar 

  65. Petroff, O. A., Hyder, F., Rothman, D. L. & Mattson, R. H. Effects of gabapentin on brain GABA, homocarnosine, and pyrrolidinone in epilepsy patients. Epilepsia 41, 675–680 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Errante, L. D., Williamson, A., Spencer, D. D. & Petroff, O. A. Gabapentin and vigabatrin increase GABA in the human neocortical slice. Epilepsy Res. 49, 203–210 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Ffrench-Mullen, J. M. H., Barker, J. L. & Rogawski, M. A. Calcium current block by (−)-pentobarbital, phenobarbital and CHEB but not (+)-pentobarbital in acutely isolated CA1 neurons: comparison with effects on GABA-activated Cl− current. J. Neurosci. 13, 3211–3221 (1993).

    Article  CAS  PubMed  Google Scholar 

  68. Stefani, A., Spadoni, F., Siniscalchi, A. & Bernardi, G. Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications. Eur. J. Pharmacol. 307, 113–116 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Wang, S. -J., Huang, C. -C., Hsu, K. -S., Tsai, J. -J. & Gean, P. -W. Inhibition of N-type calcium currents by lamotrigine in rat amygdalar neurones. Neuroreport 7, 3037–3040 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Zona, C. et al. Levetiracetam does not modulate neuronal voltage-gated Na+ and T-type Ca2+ currents. Seizure 10, 279–286 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Niespodziany, I., Klitgaard, H. & Margineanu, D. G. Levetiracetam inhibits the high-voltage-activated Ca2+ current in pyramidal neurones of rat hippocampal slices. Neurosci. Lett. 306, 5–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Lukyanetz, E. A., Shkryl, V. M. & Kostyuk, P. G. Selective blockade of N-type calcium channels by levetiracetam. Epilepsia 43, 9–18 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Perez-Reyes, E. Molecular physiology of low-voltage-activated T-type calcium channels. Physiol. Rev. 83, 117–161 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Huguenard, J. R. Low-threshold calcium currents in central nervous system neurons. Annu. Rev. Physiol. 58, 329–358 (1996).

    Article  CAS  PubMed  Google Scholar 

  75. Suzuki, S. & Rogawski, M. A. T-type calcium channels mediate the transition between tonic and phasic firing in thalamic neurons. Proc. Natl Acad. Sci. USA 86, 7228–7232 (1989).

    Article  CAS  PubMed  Google Scholar 

  76. Talley, E. M. et al. Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J. Neurosci. 19, 1895–1911 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Kim, D. et al. Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking α1G T-type Ca2+ channels. Neuron 31, 35–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Tsakiridou, E., Bertollini, L., de Curtis, M., Avanzini, G. & Pape, H. C. Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J. Neurosci. 15, 3110–3117 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Talley, E. M., Solorzano, G., Depaulis, A., Perez-Reyes, E. & Bayliss, D. A. Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat. Brain Res. Mol. Brain Res. 75, 159–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Chen, Y. et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann. Neurol. 54, 239–243 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Khosravani, H. et al. Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J. Biol. Chem. 279, 9681–9684 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Heron, S. E. et al. Genetic variation of CACNA1H in idiopathic generalized epilepsy. Ann. Neurol. 55, 595–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Coulter, D. A., Huguenard, J. R. & Prince, D. A. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic relay neurons. Ann. Neurol. 25, 582–593 (1989). The inhibitory effect of ethosuximide on T-type calcium channels is hypothesized to account for its anti-absence activity.

    Article  CAS  PubMed  Google Scholar 

  84. Gomora, J. C., Daud, A. N., Weiergräber, M. & Perez-Reyes, E. Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol. Pharmacol. 60, 1121–1132 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. McLean, M. J. & Macdonald, R. L. Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J. Pharmacol. Exp. Ther. 237, 1001–1011 (1986).

    CAS  PubMed  Google Scholar 

  86. Leresche, N. et al. On the action of the anti-absence drug ethosuximide in the rat and cat thalamus. J. Neurosci. 18, 4842–4853 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Manning, J. P., Richards, D. A., Leresche, N., Crunelli, V. & Bowery, N. G. Cortical-area specific block of genetically determined absence seizures by ethosuximide. Neuroscience 123, 5–9 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Kito, M., Maehara, M. & Watanabe, K. Mechanisms of T-type calcium channel blockade by zonisamide. Seizure 5, 115–119 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. Galarreta, M. & Hestrin, S. Frequency-dependent synaptic depression and the balance of excitation and inhibition in the neocortex. Nature Neurosci. 1, 587–594 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Miles, R. & Wong, R. K. Inhibitory control of local excitatory circuits in the guinea-pig hippocampus. J. Physiol. (Lond.) 388, 611–629 (1987).

    Article  CAS  Google Scholar 

  91. Wallace, R. H. et al. Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nature Genet. 28, 49–52 (2001). This paper and reference 92 were the first to identify mutations in GABA A receptor subunits as a genetic basis of epilepsy.

    CAS  PubMed  Google Scholar 

  92. Baulac, S. et al. First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene. Nature Genet. 28, 46–48 (2001).

    CAS  PubMed  Google Scholar 

  93. Kananura, C. et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch. Neurol. 59, 1137–1141 (2002).

    Article  PubMed  Google Scholar 

  94. Harkin, L. A. et al. Truncation of the GABAA-receptor γ2 subunit in a family with generalized epilepsy with febrile seizures plus. Am. J. Hum. Genet. 70, 530–536 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Bianchi, M. T., Song, L., Zhang, H. & Macdonald, R. L. Two different mechanisms of disinhibition produced by GABAA receptor mutations linked to epilepsy in humans. J. Neurosci. 22, 5321–5327 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Cossette, P. et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nature Genet. 31, 184–189 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Gallagher, J. P., Higashi, H. & Nishi, S. Characterization and ionic basis of GABA-induced depolarizations recorded in vitro from cat primary afferent neurones. J. Physiol. (Lond.) 275, 263–282 (1978).

    Article  CAS  Google Scholar 

  98. Akaike, N., Inomata, N. & Yakushiji, T. Differential effects of extra- and intracellular anions on GABA-activated currents in bullfrog sensory neurons. J. Neurophysiol. 62, 1388–1399 (1989).

    Article  CAS  PubMed  Google Scholar 

  99. Bormann, J., Hamill, O. P. & Sakmann, B. Mechanism of anion permeation through channels gated by glycine and γ-aminobutyric acid in mouse cultured spinal neurones. J. Physiol. (Lond.) 385, 243–286 (1987).

    Article  CAS  Google Scholar 

  100. Rudolph, U. et al. Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 401, 796–800 (1999). In mice engineered with a knock-in mutation (H101R) in the GABA A receptor α1 subunit that confers benzodiazepine insensitivity, the benzodiazepine diazepam failed to exhibit sedative and amnesic activity and had reduced anticonvulsant activity, whereas the anxiolytic and muscle relaxant effects were unaffected, revealing the specific behavioural functions of GABA A receptors containing the α1 subunit.

    Article  CAS  PubMed  Google Scholar 

  101. Crestani, F., Martin, J. R., Möhler, H. & Rudolph, U. Mechanism of action of the hypnotic zolpidem in vivo. Br. J. Pharmacol. 131, 1251–1256 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bai, D. et al. Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by γ-aminobutyric acidA receptors in hippocampal neurons. Mol. Pharmacol. 59, 814–824 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Sohal, V. S., Keist, R., Rudolph, U. & Huguenard, J. R. Dynamic GABAA receptor subtype-specific modulation of the synchrony and duration of thalamic oscillations. J. Neurosci. 23, 3649–3657 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Macdonald, R. L. & Olsen, R. W. GABAA receptor channels. Annu. Rev. Neurosci. 17, 569–602 (1994).

    Article  CAS  PubMed  Google Scholar 

  105. Rho, J. M., Donevan, S. D. & Rogawski, M. A. Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate. J. Pharmacol. Exp. Ther. 280, 1383–1391 (1997).

    CAS  PubMed  Google Scholar 

  106. White, H. S., Brown, S. D., Woodhead, J. H., Skeen, G. A. & Wolf, H. H. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res. 28, 167–179 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Gordey, M., DeLorey, T. M. & Olsen, R. W. Differential sensitivity of recombinant GABAA receptors expressed in Xenopus oocytes to modulation by topiramate. Epilepsia 41 (Suppl. 1), S25–29 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. De Biase, D., Barra, D., Bossa, F., Pucci, P. & John, R. A. Chemistry of the inactivation of 4-aminobutyrate aminotransferase by the antiepileptic drug vigabatrin. J. Biol. Chem. 266, 20056–20061 (1991).

    CAS  PubMed  Google Scholar 

  109. Löscher, W. & Horstermann, D. Differential effects of vigabatrin, γ-acetylenic GABA, aminooxyacetic acid, and valproate on levels of various amino acids in rat brain regions and plasma. Naunyn Schmiedeberg's Arch. Pharmacol. 349, 270–278 (1994).

    Article  Google Scholar 

  110. Jackson, M. F., Esplin, B. & Čapek, R. Reversal of the activity-dependent suppression of GABA-mediated inhibition in hippocampal slices from γ-vinyl GABA (vigabatrin)-pretreated rats. Neuropharmacology 39, 65–74 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Overstreet, L. S. & Westbrook, G. L. Paradoxical reduction of synaptic inhibition by vigabatrin. J. Neurophysiol. 86, 596–603 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Wu, Y., Wang, W. & Richerson, G. B. Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release. J. Neurophysiol. 89, 2021–2034 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Richerson, G. B. & Wu, Y. Dynamic equilibrium of neurotransmitter transporters: not just for reuptake anymore. J. Neurophysiol. 90, 1363–1374 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Löscher, W. Effect of inhibitors of GABA transaminase on the synthesis, binding, uptake, and metabolism of GABA. J. Neurochem. 34, 1603–1608 (1980).

    Article  PubMed  Google Scholar 

  115. Schuler, V. et al. Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABAB responses in mice lacking GABAB(1) . Neuron 31, 47–58 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Sarup, A., Larsson, O. M. & Schousboe, A. GABA transporters and GABA-transaminase as drug targets. Curr. Drug Target CNS Neurol. Disord. 2, 269–277 (2003).

    Article  CAS  Google Scholar 

  117. Suzdak, P. D. & Jansen, J. A. A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia 36, 612–626 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Thompson, S. M. & Gahwiler, B. H. Effects of the GABA uptake inhibitor tiagabine on inhibitory synaptic potentials in rat hippocampal slice cultures. J. Neurophysiol. 67, 1698–1701 (1992). Recordings from CA3 hippocampal pyramidal cells demonstrate that tiagabine greatly prolongs the duration of monosynaptic inhibitory synaptic potentials and can also inhibit epileptiform bursting.

    Article  CAS  PubMed  Google Scholar 

  119. Engel, D. et al. Laminar difference in GABA uptake and GAT-1 expression in rat CA1. J. Physiol. (Lond.) 512, 643–649 (1998).

    Article  CAS  Google Scholar 

  120. Jackson, M. F., Esplin, B. & Čapek, R. Activity-dependent enhancement of hyperpolarizing and depolarizing γ-aminobutyric acid (GABA) synaptic responses following inhibition of GABA uptake by tiagabine. Epilepsy Res. 37, 25–36 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S. F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999).

    CAS  PubMed  Google Scholar 

  122. Löscher, W. & Rogawski, M. in Ionotropic Glutamate Receptors as Therapeutic Targets (eds Lodge, D., Danysz, W. & Parsons, C. G.) 91–132 (F. P. Graham, Johnson City, Tennessee, 2002).

    Google Scholar 

  123. Rogawski, M. A. et al. GluR5 kainate receptors, seizures, and the amygdala. Ann. NY Acad. Sci. 985, 150–162 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Sheth, R. D. & Gidal, B. E. Refractory status epilepticus: response to ketamine. Neurology 51, 1765–1766 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. Boyd, S. G. & Dan, B. Cortical sensitivity in refractory status epilepticus. Clin. Neurophysiol. 111 (Suppl. 1), S156–164 (2000).

    Google Scholar 

  126. Mewasingh, L. D. et al. Oral ketamine in paediatric non-convulsive status epilepticus. Seizure 12, 483–489 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Subramaniam, S. et al. Felbamate block of the N-methyl-D-aspartate receptor. J. Pharmacol. Exp. Ther. 273, 878–886 (1995).

    CAS  PubMed  Google Scholar 

  128. Kuo, C. C., Lin, B. J., Chang, H. R. & Hsieh, C. P. Use-dependent inhibition of the N-methyl-D-aspartate currents by felbamate: a gating modifier with selective binding to the desensitized channels. Mol. Pharmacol. 65, 370–380 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Kleckner, N. W., Glazewski, J. C., Chen, C. C. & Moscrip, T. D. Subtype-selective antagonism of N-methyl-D–aspartate receptors by felbamate: insights into the mechanism of action. J. Pharmacol. Exp. Ther. 289, 886–894 (1999).

    CAS  PubMed  Google Scholar 

  130. Harty, T. P. & Rogawski, M. A. Felbamate block of recombinant N-methyl-D-aspartate receptors: selectivity for the NR2B subunit. Epilepsy Res. 39, 47–55 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Bleakman, D. Kainate receptor pharmacology and physiology. Cell. Mol. Life. Sci. 56, 558–566 (1999).

    Article  CAS  PubMed  Google Scholar 

  132. Lerma, J., Paternain, A. V., Rodriguez-Moreno, A. & López-Garcia, J. C. Molecular physiology of kainate receptors. Physiol. Rev. 81, 971–998 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Smolders, I. et al. Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures. Nature Neurosci. 5, 796–804 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Gryder, D. S. & Rogawski, M. A. Selective antagonism of GluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons. J. Neurosci. 23, 7069–7074 (2003). A demonstration that topiramate inhibits AMPA and kainate receptor mediated synaptic excitation, but is more potent and effective against the kainate receptor-mediated component.

    Article  CAS  PubMed  Google Scholar 

  135. Kaminski, R. M., Banerjee, M. & Rogawski, M. A. Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist. Neuropharmacology 46, 1097–1104 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Löscher, W. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and models with spontaneous recurrent seizures. Epilepsy Res. 50, 105–123 (2002).

    Article  PubMed  Google Scholar 

  137. White, H. S. Animal models of epileptogenesis. Neurology 59 (Suppl. 5), S7–14 (2002).

    Article  PubMed  Google Scholar 

  138. 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).

  139. Scheffer, I. E. & Berkovic, S. F. The genetics of human epilepsy. Trends Pharmacol. Sci. 24, 428–433 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Escayg, A. et al. Coding and noncoding variation of the human calcium-channel β4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am. J. Hum. Genet. 66, 1531–1539 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Jouvenceau A. et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 358, 801–807 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Holtmann, M., Opp, J., Tokarzewski, M. & Korn-Merker, E. Human epilepsy, episodic ataxia type 2, and migraine. Lancet 359, 170–171 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Chioza, B. et al. Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy. Eur. J. Hum. Genet. 10, 857–864 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Chioza, B. et al. Association between the α1a calcium channel gene CACNA1A and idiopathic generalized epilepsy. Neurology 56, 1245–1246 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Michael A. Rogawski

  2. Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, and Center for Systems Neuroscience, Bünteweg 17, D-30559, Hannover, Germany

    Wolfgang Löscher

Authors
  1. Michael A. Rogawski
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Wolfgang Löscher
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Michael A. Rogawski.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

CACNA1H

GABAT

GABRA1

GAD

GAT1

mGluR1

mGluR5

NR1

NR2B

FURTHER INFORMATION

Encyclopedia of Life Sciences

epilepsy

epilepsy: management

Rogawski's homepage

Glossary

ANTIEPILEPTIC DRUG

A drug that protects against the occurrence of epileptic seizures; an alternative to the term 'anticonvulsant drug'.

GENERALIZED ABSENCE SEIZURE

A non-convulsive seizure that typically occurs in childhood. It is characterized by a sudden, brief impairment of consciousness, cessation of ongoing activity without loss of postural tone, and 3 Hz rhythmic cortical discharges of geneneralized onset. The usual duration is 5–10 seconds; several episodes can occur daily.

PAROXYSMAL DEPOLARIZATION SHIFT

Abnormal prolonged depolarization with repetitive spiking characteristic of neurons in epileptic cortical zones that are reflected as interictal discharges in the electroencephalogram.

METABOTROPIC RECEPTOR

A G-protein-coupled receptor that may indirectly influence the activity of ion channels but does not itself serve as a channel.

GENERALIZED TONIC-CLONIC SEIZURE

A convulsive seizure involving the entire body, usually characterized by muscle rigidity, violent rhythmic muscle contractions and loss of consciousness.

PARTIAL SEIZURE

Seizure resulting from a localized brain disturbance; also referred to as 'focal seizure'.

SODIUM CHANNEL INACTIVATION

Entry of the sodium channel into a set of states that are distinct from the open and closed states that prevents the channel from reopening until there has been sufficient time for recovery, thereby preventing persistent sodium flux during long depolarizations.

GEFS+

A pleotropic autosomal dominant epilepsy syndrome in which there are febrile seizures in childhood and afebrile generalized seizures that persist beyond 6 years of age, including absences, myoclonic seizures, atonic seizures and myoclonic-astatic seizures. The syndrome is distinct from common benign febrile seizures.

ICTAL

Relating to an epileptic seizure.

INTERICTAL DISCHARGES

Distinctive waves or complexes that can be recorded between seizures in the electroencephalogram of individuals with epilepsy. Generally brief in duration, but can have various morphologies described as 'sharp wave', 'spike' or 'spike-and-slow-wave'.

PERSISTENT SODIUM CURRENT

A small component of the sodium current that does not inactivate.

POLYGENIC

A characteristic that is controlled by different genes, each of which has only a small role in the phenotype.

UREIDE RING

Heterocyclic ring formed from urea (CO(NH2)2) as in phenytoin and barbiturates. In ethosuximide, the hydantoin ureide ring of phenytoin is substituted for a succinimide ring with a single nitrogen atom.

IONOTROPIC RECEPTOR

Possessing an intrinsic channel (pore) that mediates transmembrane ion flux.

MYOCLONIC SEIZURE

Sudden, brief, involuntary spasm (contraction–relaxation) of the tongue or muscles of the face, trunk, arms, legs or the entire body.

DRAVET'S SYNDROME

A rare intractable epilepsy syndrome in which prolonged generalized tonic, clonic or tonic-clonic seizures occur between 2 and 9 months of age followed by myoclonic, tonic-clonic, absence and partial seizures in the second year of life. The syndrome is associated with delayed psychomotor and speech development, and ataxia.

JUVENILE MYOCLONIC EPILEPSY

A common generalized epilepsy syndrome presenting between the ages of 8 and 26 years with early morning myoclonus, mainly affecting the upper extremities, and often associated with generalized tonic-clonic seizures and less frequently with absence seizures.

STATUS EPILEPTICUS

Continuous seizure activity without recovery of consciousness or return to neurological function.

IRREVERSIBLE SUICIDE INHIBITOR

An inhibitor that is inactive until acted upon by the enzyme: the inhibitor binds to the enzyme as a substrate and a chemically reactive intermediate is generated that inactivates the enzyme.

LENNOX-GASTAUT SYNDROME

A devastating paediatric epilepsy syndrome usually beginning between ages 1 to 8 years. It is characterized by multiple seizure types including tonic, atonic, atypical absence and myoclonic seizures. There is often impaired intellectual functioning and behavioural disturbances.

ANTIEPILEPTOGENIC

Protection against the development of epilepsy, a state characterized by recurrent seizures.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rogawski, M., Löscher, W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5, 553–564 (2004). https://doi.org/10.1038/nrn1430

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1430

Search

Advanced 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
pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy