This Article Abstract Free Full Text (Free PDF) Free Erratum for Surges et al. Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Surges, R. Articles by Walker, M. C. Search for Related Content Social Bookmarking                         What's this?

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London, r.surges{at}ion.ucl.ac.uk

Kirill E. Volynski

Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London

Matthew C. Walker

Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College of London

Levetiracetam (LEV) is a new antiepileptic drug that is clinically effective in generalized and partial epilepsy syndromes as sole or add-on medication. Nevertheless, its underlying mechanism of action is poorly understood. It has a unique preclinical profile; unlike other antiepileptic drugs (AEDs), it modulates seizure-activity in animal models of chronic epilepsy with no effect in most animal models of acute seizures. Yet it is effective in acute in-vitro `seizure' models. A possible explanation for these dichotomous findings is that LEV has different mechanisms of actions, whether given acutely or chronically and in `epileptic' and control tissue. Here we review the general mechanism of action of AEDs, give an updated and critical overview about the experimental findings of LEV's cellular targets (in particular the synaptic vesicular protein SV2A) and ask whether LEV represents a new class of AED.

Key Words: levetiracetam • SV2A • antiepileptic drugs • synaptic transmission • epilepsy • ion channels

References

• Ambrosio, A.F., Silva, A.P., Malva, J.O., Soares-da-Silva, P., Carvalho, A.P. and Carvalho, C.M. (1999) Carbamazepine inhibits L-type Ca2+ channels in cultured rat hippocampal neurons stimulated with glutamate receptor agonists. Neuropharmacology 38: 1349-1359.[CrossRef][Medline] [Order article via Infotrieve]
• Angehagen, M., Margineanu, D.G., Ben-Menachem, E., Rönnbäck, L., Hansson, E. and Klitgaard, H. (2003) Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons. Neuroreport 14: 471-475.[CrossRef][Medline] [Order article via Infotrieve]
• Angehagen, M., Ben-Menachem, E., Shank, R., Rönnbäck, L. and Hansson, E. (2004) Topiramate modulation of kainate-induced calcium currents is inversely related to channel phosphorylation level. J Neurochem 88: 320-325.[Medline] [Order article via Infotrieve]
• Bardo, S., Cavazzini, M.G. and Emptage, N. (2006) The role of the endoplasmic reticulum Ca2+ store in the plasticity of central neurons. Trends Pharmacol Sci 27: 78-84.[CrossRef][Medline] [Order article via Infotrieve]
• Barton, M.E., Klein, B.D., Wolf, H.H. and White, H.S. (2001) Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res 47: 217-227.[CrossRef][Medline] [Order article via Infotrieve]
• Bimstiel, S., Wülfert, E. and Beck, S.G. (1997) Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission. Nauuyn Schmiedebergs Arch Pharmacol 356: 611-618.[CrossRef]
• Bonnet, U., Bingmann, D. and Wiemann, M. (2000) Intracellular pH modulates spontaneous and epileptiform bioelectric activity of hippocampal CA3-neurones. Eur Neuropsychopharmacol 10: 97-103.[CrossRef][Medline] [Order article via Infotrieve]
• Bormann, J. (2000) The `ABC' of GABA receptors. Trends Pharmacol Sci 21: 16-19.[CrossRef][Medline] [Order article via Infotrieve]
• Carunchio, I., Pieri, M., Ciotti, M.T., Albo, F. and Zona, C. (2007) Modulation of AMPA receptors in cultured cortical neurons induced by the antiepileptic drug levetiracetam. Epilepsia 48: 654-662.[Medline] [Order article via Infotrieve]
• Cataldi, M., Lariccia, V., Secondo, A., di Renzo, G. and Annunziato, L. (2005) The antiepileptic drug levetiracetam decreases the inositol 1,4,5-trisphosphate-dependent [Ca2+]I increase induced by ATP and bradykinin in PC12 cells. J Pharmacol Exp Ther 313: 720-730.[Abstract/Free Full Text]
• Catterall, W.A. (2000a) From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26: 13-25.[CrossRef][Medline] [Order article via Infotrieve]
• Catterall, W.A. (2000b) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16: 521-555.[CrossRef][Medline] [Order article via Infotrieve]
• Costa, C., Martella, G., Picconi, B., Prosperetti, C., Pisani, A., Di Filippo, M. et al. (2006) Multiple mechanisms underlying the neuroprotective effects of antiepileptic drugs against in vitro ischemia. Stroke 37: 1319-1326.[Abstract/Free Full Text]
• Coulter, D.A. (2000) Mossy fiber zinc and temporal lobe epilepsy: pathological association with altered `epileptic' gamma-aminobutyric acid A receptors in dentate granule cells. Epilepsia 41: S96-S99.[CrossRef][Medline] [Order article via Infotrieve]
• Crowder, K.M., Gunther, J.M., Jones, T.A., Hale, B.D., Zhang, H.Z., Peterson, M.R. et al. (1999) Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proc Natl Acad Sci USA 96: 15268-15273.[Abstract/Free Full Text]
• Custer, K.L., Austin, N.S., Sullivan, J.M. and Bajjalieh, S.M. (2006) Synaptic vesicle protein 2 enhances release probability at quiescent synapses. J Neurosci 26: 1303-1313.[Abstract/Free Full Text]
• De Smedt, T., Raedt, R., Vonck, K. and Boon, P. (2007) Levetiracetam: part II, the clinical profile of a novel anticonvulsant drug. CNS Drug Rev 13: 57-78.[CrossRef][Medline] [Order article via Infotrieve]
• Dooley, D.J., Taylor, C.P., Donevan, S. and Feltner, D. (2007) Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharmacol Sci 28: 75-82.[CrossRef][Medline] [Order article via Infotrieve]
• Errington, A.C., Stöhr, T., Heers, C. and Lees, G. (2008) The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 73(1): 157-169.[Abstract/Free Full Text]
• Gale, K. and Iadarola, M.J. (1980) Seizure protection and increased nerve-terminal GABA: delayed effects of GABA transaminase inhibition. Science 208: 288-291.[Abstract/Free Full Text]
• Glien, M., Brandt, C., Potschka, H. and 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: 350-357.[Medline] [Order article via Infotrieve]
• Gomora, J.C., Daud, A.N., Weiergraber, M. and Perez-Reyes, E. (2001) Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol 60: 1121-1132.[Abstract/Free Full Text]
• Gorji, A., Höhling, J.M., Madeja, M., Straub, H., Köhling, R., Tuxhorn, I. et al. (2002) Effect of levetiracetam on epileptiform discharges in human neocortical slices. Epilepsia 43: 1480-1487.[Medline] [Order article via Infotrieve]
• Jan, L.Y. and Jan, Y.N. (1997) Cloned potassium channels from eukaryotes and prokaryotes. Annu Rev Neurosci 20: 91-123.[CrossRef][Medline] [Order article via Infotrieve]
• Janz, R., Goda, Y., Geppert, M., Missler, M. and Südhof, T.C. (1999) SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron 24: 1003-1016.[CrossRef][Medline] [Order article via Infotrieve]
• Kaminski, R.M., Matagne, A., Leclercq, K., Gillard, M., Michel, P., Kenda, B. et al. (2008) SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 54: 715-720.[CrossRef][Medline] [Order article via Infotrieve]
• Klitgaard, H., Matagne, A., Gobert, J. and Wülfert, E. (1998) Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol 353: 191-206.[CrossRef][Medline] [Order article via Infotrieve]
• Knake, S., Gruener, J., Hattemer, K., Klein, K.M., Bauer, S., Oertel, W.H. et al. (2008) Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J Neurol Neurosurg Psychiatry 79: 588-589.[Abstract/Free Full Text]
• Kuo, C.C. (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol Pharmacol 54: 712-721.[Abstract/Free Full Text]
• Lampl, I., Schwindt, P. and Crill, W. (1998) Reduction of cortical pyramidal neuron excitability by the action of phenytoin on persistent Na+ current. J Pharmacol Exp Ther 284: 228-237.[Abstract/Free Full Text]
• Leniger, T., Thöne, J., Bonnet, U., Hufnagel, A., Bingmann, D. and Wiemann, M. (2004) Levetiracetam inhibits Na+-dependent Cl-/HCO3- exchange of adult hippocampal CA3 neurons from guinea-pigs. Br J Pharmacol 142: 1073-1080.[CrossRef][Medline] [Order article via Infotrieve]
• Löscher, W. (1989) Valproate enhances GABA turnover in the substantia nigra. Brain Res 501: 198-203.[CrossRef][Medline] [Order article via Infotrieve]
• Löscher, W. and Hönack, D. (1993) 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.[CrossRef][Medline] [Order article via Infotrieve]
• Löscher, W., Hönack, D. and Bloms-Funke, P. (1996) The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata. Brain Res 735: 208-216.[Medline] [Order article via Infotrieve]
• Löscher, W. and Hönack, D. (2000) Development of tolerance during chronic treatment of kindled rats with the novel antiepileptic drug levetiracetam. Epilepsia 41: 1499-1506.[Medline] [Order article via Infotrieve]
• Löscher, W., Reissmüller, E. and Ebert, U. (2000) Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats. Epilepsy Res 40: 63-77.[CrossRef][Medline] [Order article via Infotrieve]
• Lukyanetz, E.A., Shkryl, V.M. and Kostyuk, P.G. (2002) Selective blockade of N-type calcium channels by levetiracetam. Epilepsia 43: 9-18.[Medline] [Order article via Infotrieve]
• Lynch, B.A., Lambeng, N., Nocka, K., Kensel-Hammes, P., Bajjalieh, S.M., Matagne, A. et al. (2004) The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 101: 9861-9866.[Abstract/Free Full Text]
• Madeja, M., Margineanu, D.G., Gorji, A., Siep, E., Boerrigter, P., Klitgaard, H. et al. (2003) Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action? Neuropharmacology 45: 661-671.[CrossRef][Medline] [Order article via Infotrieve]
• Margineanu, D.G. and Wülfert, E. (1995) ucb L059, a novel anticonvulsant, reduces bicuculline-induced hyperexcitability in rat hippocampal CA3 in vivo. Eur J Pharmacol 286: 321-325.[CrossRef][Medline] [Order article via Infotrieve]
• Margineanu, D.G. and Klitgaard, H. (2003) Levetiracetam has no significant gamma-aminobutyric acid-related effect on paired-pulse interaction in the dentate gyrus of rats. Eur J Pharmacol 466: 255-261.[CrossRef][Medline] [Order article via Infotrieve]
• McCormick, D.A. and Contreras, D. (2001) On the cellular and network basis of epileptic seizures. Annu Rev Physiol 63: 815-846.[CrossRef][Medline] [Order article via Infotrieve]
• McLean, M.J. and Macdonald, R.L. (1983) Multiple actions of phenytoin on mouse spinal cord neurons in cell culture. J Pharmacol Exp Ther 227: 779-789.[Abstract/Free Full Text]
• Mehta, A.K. and Ticku, M.K. (1999) An update on GABAA receptors. Brain Res Brain Res Rev 29: 196-217.[CrossRef][Medline] [Order article via Infotrieve]
• Niespodziany, I., Klitgaard, H. and Margineanu, D.G. (2001) Levetiracetam inhibits the high-voltage-activated Ca(2+) current in pyramidal neurones of rat hippocampal slices. Neurosci Lett 306: 5-8.[CrossRef][Medline] [Order article via Infotrieve]
• Niespodziany, I., Klitgaard, H. and Margineanu, D.G. (2003) Desynchronizing effect of levetiracetam on epileptiform responses in rat hippocampal slices. Neuroreport 14: 1273-1276.[CrossRef][Medline] [Order article via Infotrieve]
• Niespodziany, I., Klitgaard, H. and Margineanu, D.G. (2004) Is the persistent sodium current a specific target of anti-absence drugs? Neuroreport 15: 1049-1052.[CrossRef][Medline] [Order article via Infotrieve]
• Nobile, M. and Lagostena, L. (1998) A discriminant block among K+ channel types by phenytoin in neuroblastoma cells. Br J Pharmacol 124: 1698-1702.[CrossRef][Medline] [Order article via Infotrieve]
• Pal, S., Sun, D., Limbrick, D., Rafiq, A. and DeLorenzo, R.J. (2001) Epileptogenesis induces long-term alterations in intracellular calcium release and sequestration mechanisms in the hippocampal neuronal culture model of epilepsy. Cell Calcium 30: 285-296.[CrossRef][Medline] [Order article via Infotrieve]
• Palma, E., Ragozzino, D., Di Angelantonio, S., Mascia, A., Maiolino, F., Manfredi, M. et al. (2007) The antiepileptic drug levetiracetam stabilizes the human epileptic GABAA receptors upon repetitive activation. Epilepsia 48: 1842-1849.[Medline] [Order article via Infotrieve]
• Patsalos, P.N. (2000) Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 85: 77-85.[CrossRef][Medline] [Order article via Infotrieve]
• Pisani, A., Bonsi, P., Martella, G., De Persis, C., Costa, C., Pisani, F. et al. (2004) Intracellular calcium increase in epileptiform activity: modulation by levetiracetam and lamotrigine. Epilepsia 45: 719-728.[Medline] [Order article via Infotrieve]
• Poolos, N.P., Migliore, M. and Johnston, D. (2002) Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 5: 767-774.[Medline] [Order article via Infotrieve]
• Potschka, H., Baltes, S. and Löscher, W. (2004) Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats. Epilepsy Res 58: 85-91.[CrossRef][Medline] [Order article via Infotrieve]
• Poulain, P. and Margineanu, D.G. (2002) Levetiracetam opposes the action of GABAA antagonists in hypothalamic neurones. Neuropharmacology 42: 346-352.[CrossRef][Medline] [Order article via Infotrieve]
• Ramael, S., Daoust, A., Otoul, C., Toublanc, N., Troenaru, M., Lu, Z.S. et al. (2006) Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study. Epilepsia 47: 1128-1135.[Medline] [Order article via Infotrieve]
• Rambeck, B., Jürgens, U.H., May, T.W., Pannek, H.W., Behne, F., Ebner, A. et al. (2006) Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy. Epilepsia 47: 681-694.[CrossRef][Medline] [Order article via Infotrieve]
• Rekling, J.C., Jahnsen, H. and Mosfeldt Laursen, A. (1990) The effect of two lipophilic gamma-aminobutyric acid uptake blockers in CA1 of the rat hippocampal slice. Br J Pharmacol 99: 103-106.[Medline] [Order article via Infotrieve]
• Rigo, J.M., Hans, G., Nguyen, L., Rocher, V., Belachew, S., Malgrange, B. et al. (2002) The antiepileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol 136: 659-672.[CrossRef][Medline] [Order article via Infotrieve]
• Robinson, R.B. and Siegelbaum, S.A. (2003) Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 65: 453-480.[CrossRef][Medline] [Order article via Infotrieve]
• Sawada, S. and Yamamoto, C. (1985) Blocking action of pentobarbital on receptors for excitatory amino acids in the guinea pig hippocampus. Exp Brain Res 59: 226-231.[Medline] [Order article via Infotrieve]
• Shannon, H.E., Eberle, E.L. and Peters, S.C. (2005) Comparison of the effects of anticonvulsant drugs with diverse mechanisms of action in the formalin test in rats. Neuropharmacology 48: 1012-1020.[CrossRef][Medline] [Order article via Infotrieve]
• Sills, G.J., Leach, J.P., Fraser, C.M., Forrest, G., Patsalos, P.N. and Brodie, M.J. (1997) Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. Eur J Pharmacol 325: 35-40.[CrossRef][Medline] [Order article via Infotrieve]
• Simeone, T.A., Wilcox, K.S. and White, H.S. (2006) Subunit selectivity of topiramate modulation of heteromeric GABA(A) receptors. Neuropharmacology 50: 845-857.[CrossRef][Medline] [Order article via Infotrieve]
• Subramaniam, S., Donevan, S.D. and Rogawski, M.A. (1996) Block of the N-methyl-D-aspartate receptor by remacemide and its des-glycine metabolite. J Pharmacol Exp Ther 276: 161-168.[Abstract/Free Full Text]
• Surges, R., Freiman, T.M. and Feuerstein, T.J. (2003) Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells. Epilepsia 44: 150-156.[CrossRef][Medline] [Order article via Infotrieve]
• Suzuki, S., Kawakami, K., Nishimura, S., Watanabe, Y., Yagi, K., Seino, M. et al. (1992) Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex. Epilepsy Res 12: 21-27.[CrossRef][Medline] [Order article via Infotrieve]
• Tatulian, L., Delmas, P., Abogadi, F.C. and Brown, D.A. (2001) Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci 21: 5535-5545.[Abstract/Free Full Text]
• Todorovic, S.M. and Lingle, C.J. (1998) Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents. J Neurophysiol 79: 240-252.[Abstract/Free Full Text]
• Van Vliet, E.A., van Schaik, R., Edelbroek, P.M., Lopes da Silva, F.H., Wadman, W.J. and Gorter, J.A. (2008) Development of tolerance to levetiracetam in rats with chronic epilepsy. Epilepsia [Epub ahead of print].
• Walker, M.C. and Fisher, A. (2004) Mechanisms of antiepileptic drug action. In Shorvon, S.D., Perucca, E., Fish, D.R. and Dodson, W.E. (eds), The Treatment of Epilepsy. Blackwell: Oxford.
• Walker, M.C., Chan, D. and Thom, M. (2007) Hippocampus and human disease. In Andersen, P., Morris, R., Amaral, D., Bliss, T. and Okeefe, J. (eds), The hippocampus book. OUP: Oxford.
• White, H.S., Harmsworth, W.L., Sofia, R.D. and Wolf, H.H. (1995) Felbamate modulates the strychnine-insensitive glycine receptor. Epilepsy Res 20: 41-48.[CrossRef][Medline] [Order article via Infotrieve]
• Wuttke, T.V., Seebohm, G., Bail, S., Maljevic, S. and Lerche, H. (2005) The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol 67: 1009-1017.[Abstract/Free Full Text]
• Yang, X.F., Weisenfeld, A. and Rothman, S.M. (2007) Prolonged exposure to levetiracetam reveals a presynaptic effect on neurotransmission. Epilepsia 48: 1861-1869.[Medline] [Order article via Infotrieve]
• Zona, C., Niespodziany, I., Marchetti, C., Klitgaard, H., Bernardi, G. and Margineanu, D.G. (2001) Levetiracetam does not modulate neuronal voltage-gated Na+ and T-type Ca2+ currents. Seizure 10: 279-286.[CrossRef][Medline] [Order article via Infotrieve]

Therapeutic Advances in Neurological Disorders, Vol. 1, No. 1, 13-24 (2008)
DOI: 10.1177/1756285608094212


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This Article Abstract Free Full Text (Free PDF) Free Erratum for Surges et al. Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Surges, R. Articles by Walker, M. C. Search for Related Content Social Bookmarking                         What's this?