Skip to main content

Advertisement

SpringerLink
Log in

Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications (ASMs). Although dozens of ASMs are available in the clinic, approximately 30% of epileptic patients have medically refractory seizures; other limitations in most traditional ASMs include poor tolerability and drug-drug interactions. Therefore, there is an urgent need to develop alternative ASMs. Levetiracetam (LEV) is a first-line ASM that is well tolerated, has promising efficacy, and has little drug-drug interaction. Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein (SV) 2A, the molecular basis of its action remains unknown. Even so, the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success. This review highlights the research and development (R&D) process of LEV and its analogs, brivaracetam and padsevonil, to provide ideas and experience for the R&D of novel ASMs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Reference

  1. Thijs RD, Surges R, O’Brien TJ, Sander JW. Epilepsy in adults. Lancet 2019, 393: 689–701.

    Article  PubMed  Google Scholar 

  2. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: Clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev 2020, 72: 606–638.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Nabbout R, Kuchenbuch M. Impact of predictive, preventive and precision medicine strategies in epilepsy. Nat Rev Neurol 2020, 16: 674–688.

    Article  PubMed  Google Scholar 

  4. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. J Jpn Epilepsy Soc 2019, 37: 6–14.

    Article  Google Scholar 

  5. Devinsky O, Vezzani A, O’Brien TJ, Jette N, Scheffer IE, de Curtis M, et al. Epilepsy. Nat Rev Dis Primers 2018, 4: 18024.

    Article  PubMed  Google Scholar 

  6. Rogawski MA, Löscher W, Rho JM. Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med 2016, 6: a022780.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sills GJ, Rogawski MA. Mechanisms of action of currently used antiseizure drugs. Neuropharmacology 2020, 168: 107966.

    Article  CAS  PubMed  Google Scholar 

  8. Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics 2007, 4: 18–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Löscher W, Klitgaard H, Twyman RE, Schmidt D. New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov 2013, 12: 757–776.

    Article  PubMed  Google Scholar 

  10. Krakow K, Walker M, Otoul C, Sander JW. Long-term continuation of levetiracetam in patients with refractory epilepsy. Neurology 2001, 56: 1772–1774.

    Article  CAS  PubMed  Google Scholar 

  11. Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: A systematic review and meta-analysis. Neurology 2016, 86: 1344–1352.

    Article  PubMed  Google Scholar 

  12. French JA, Costantini C, Brodsky A, von Rosenstiel P. Adjunctive brivaracetam for refractory partial-onset seizures: A randomized, controlled trial. Neurology 2010, 75: 519–525.

    Article  CAS  PubMed  Google Scholar 

  13. Rademacher M, Toledo M, Van Paesschen W, Liow KK, Milanov IG, Esch ML, et al. Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials. Epilepsia Open 2022, 7: 758–770.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Buckley K, Kelly RB. Identification of a transmembrane glycoprotein specific for secretory vesicles of neural and endocrine cells. J Cell Biol 1985, 100: 1284–1294.

    Article  CAS  PubMed  Google Scholar 

  15. Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH. Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J Neurosci 1994, 14: 5223–5235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Howes OD, Cummings C, Chapman GE, Shatalina E. Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes. Neuropsychopharmacology. 2023, 48: 151–167.

    Article  PubMed  Google Scholar 

  17. Pazarlar BA, Aripaka SS, Petukhov V, Pinborg L, Khodosevich K, Mikkelsen JD. Expression profile of synaptic vesicle glycoprotein 2A, B, and C paralogues in temporal neocortex tissue from patients with temporal lobe epilepsy (TLE). Mol Brain 2022, 15: 45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rossi R, Arjmand S, Bærentzen SL, Gjedde A, Landau AM. Synaptic vesicle glycoprotein 2A: Features and functions. Front Neurosci 2022, 16: 864514.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rogawski MA. A new SV2A ligand for epilepsy. Cell 2016, 167: 587.

    Article  CAS  PubMed  Google Scholar 

  20. Klitgaard H, Verdru P. Levetiracetam: The first SV2A ligand for the treatment of epilepsy. Expert Opin Drug Discov 2007, 2: 1537–1545.

    Article  CAS  PubMed  Google Scholar 

  21. De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: The profile of a novel anticonvulsant drug-part I: Preclinical data. CNS Drug Rev 2007, 13: 43–56.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004, 101: 9861–9866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kaminski RM, Matagne A, Leclercq K, Gillard M, Michel P, Kenda B, et al. 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 2008, 54: 715–720.

    Article  CAS  PubMed  Google Scholar 

  24. Gillard M, Chatelain 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 2006, 536: 102–108.

    Article  CAS  PubMed  Google Scholar 

  25. Harada S, Tanaka S, Takahashi Y, Matsumura H, Shimamoto C, Nakano T, et al. Inhibition of Ca(2+)-regulated exocytosis by levetiracetam, a ligand for SV2A, in antral mucous cells of Guinea pigs. Eur J Pharmacol 2013, 721: 185–192.

    Article  CAS  PubMed  Google Scholar 

  26. Kaminski RM, Gillard M, Leclercq K, Hanon E, Lorent G, Dassesse D, et al. Proepileptic phenotype of SV2A-deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam. Epilepsia 2009, 50: 1729–1740.

    Article  CAS  PubMed  Google Scholar 

  27. Nowack A, Malarkey EB, Yao J, Bleckert A, Hill J, Bajjalieh SM. Levetiracetam reverses synaptic deficits produced by overexpression of SV2A. PLoS One 2011, 6: e29560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bajjalieh SM, Peterson K, Shinghal R, Scheller RH. SV2, a brain synaptic vesicle protein homologous to bacterial transporters. Science 1992, 257: 1271–1273.

    Article  CAS  PubMed  Google Scholar 

  29. Feany MB, Lee S, Edwards RH, Buckley KM. The synaptic vesicle protein SV2 is a novel type of transmembrane transporter. Cell 1992, 70: 861–867.

    Article  CAS  PubMed  Google Scholar 

  30. Ciruelas K, Marcotulli D, Bajjalieh SM. Synaptic vesicle protein 2: A multi-faceted regulator of secretion. Semin Cell Dev Biol 2019, 95: 130–141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chang WP, Südhof TC. SV2 renders primed synaptic vesicles competent for Ca2+-induced exocytosis. J Neurosci 2009, 29: 883–897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Custer KL, Austin NS, Sullivan JM, Bajjalieh SM. Synaptic vesicle protein 2 enhances release probability at quiescent synapses. J Neurosci 2006, 26: 1303–1313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Madeo M, Kovács AD, Pearce DA. The human synaptic vesicle protein, SV2A, functions as a galactose transporter in Saccharomyces cerevisiae. J Biol Chem 2014, 289: 33066–33071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xu T, Bajjalieh SM. SV2 modulates the size of the readily releasable pool of secretory vesicles. Nat Cell Biol 2001, 3: 691–698.

    Article  CAS  PubMed  Google Scholar 

  35. Vogl C, Tanifuji S, Danis B, Daniels V, Foerch P, Wolff C, et al. Synaptic vesicle glycoprotein 2A modulates vesicular release and calcium channel function at peripheral sympathetic synapses. Eur J Neurosci 2015, 41: 398–409.

    Article  PubMed  Google Scholar 

  36. Yao J, Nowack A, Kensel-Hammes P, Gardner RG, Bajjalieh SM. Cotrafficking of SV2 and synaptotagmin at the synapse. J Neurosci 2010, 30: 5569–5578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Harper CB, Small C, Davenport EC, Low DW, Smillie KJ, Martínez-Mármol R, et al. An epilepsy-associated SV2A mutation disrupts synaptotagmin-1 expression and activity-dependent trafficking. J Neurosci 2020, 40: 4586–4595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang N, Gordon SL, Fritsch MJ, Esoof N, Campbell DG, Gourlay R, et al. Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1. J Neurosci 2015, 35: 2492–2507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sudhof TC. The synaptic vesicle cycle. Annu Rev Neurosci 2004, 27: 509–547.

    Article  PubMed  Google Scholar 

  40. Martens S, Kozlov MM, McMahon HT. How synaptotagmin promotes membrane fusion. Science 2007, 316: 1205–1208.

    Article  CAS  PubMed  Google Scholar 

  41. Hui E, Johnson CP, Yao J, Yao J, Chapman ER. Synaptotagmin-mediated bending of the target membrane is a critical step in Ca(2+)-regulated fusion. Cell 2009, 138: 709–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schivell AE, Mochida S, Kensel-Hammes P, Custer KL, Bajjalieh SM. SV2A and SV2C contain a unique synaptotagmin-binding site. Mol Cell Neurosci 2005, 29: 56–64.

    Article  CAS  PubMed  Google Scholar 

  43. Schivell AE, Batchelor RH, Bajjalieh SM. Isoform-specific, calcium-regulated interaction of the synaptic vesicle proteins SV2 and synaptotagmin. J Biol Chem 1996, 271: 27770–27775.

    Article  CAS  PubMed  Google Scholar 

  44. Li YC, Kavalali ET. Synaptic vesicle-recycling machinery components as potential therapeutic targets. Pharmacol Rev 2017, 69: 141–160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Crowder KM, Gunther JM, Jones TA, Hale BD, Zhang HZ, Peterson MR, et al. Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proc Natl Acad Sci USA 1999, 96: 15268–15273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Janz R, Goda Y, Geppert M, Missler M, Südhof TC. SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron 1999, 24: 1003–1016.

    Article  CAS  PubMed  Google Scholar 

  47. Joensuu M, Syed P, Saber SH, Lanoue V, Wallis TP, Rae J, et al. Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG-Syt1-SV2 plasma membrane nanocluster for synaptic vesicle entry. EMBO J 2023, 42: e112095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu Z, Lee PG, Krez N, Lam KH, Liu H, Przykopanski A, et al. Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2. Nat Commun 2023, 14: 2338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dong M, Yeh F, Tepp WH, Dean C, Johnson EA, Janz R, et al. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006, 312: 592–596.

    Article  CAS  PubMed  Google Scholar 

  50. Yeh FL, Dong M, Yao J, Tepp WH, Lin G, Johnson EA, et al. SV2 mediates entry of tetanus neurotoxin into central neurons. PLoS Pathog 2010, 6: e1001207.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Stout KA, Dunn AR, Hoffman C, Miller GW. The synaptic vesicle glycoprotein 2: Structure, function, and disease relevance. ACS Chem Neurosci 2019, 10: 3927–3938.

    Article  CAS  PubMed  Google Scholar 

  52. Reigada D, Díez-Pérez I, Gorostiza P, Verdaguer A, Gómez de Aranda I, Pineda O, et al. Control of neurotransmitter release by an internal gel matrix in synaptic vesicles. Proc Natl Acad Sci USA 2003, 100: 3485–3490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shorvon S. Pyrrolidone derivatives. Lancet 2001, 358: 1885–1892.

    Article  CAS  PubMed  Google Scholar 

  54. Kenda BM, Matagne AC, Talaga PE, Pasau PM, Differding E, Lallemand BI, et al. Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. J Med Chem 2004, 47: 530–549.

    Article  CAS  PubMed  Google Scholar 

  55. 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 1998, 353: 191–206.

    Article  CAS  PubMed  Google Scholar 

  56. Gower AJ, Noyer M, Verloes R, Gobert J, Wülfert E. Ucb L059, a novel anti-convulsant drug: Pharmacological profile in animals. Eur J Pharmacol 1992, 222: 193–203.

    Article  CAS  PubMed  Google Scholar 

  57. Zona C, Niespodziany I, Marchetti C, Klitgaard H, Bernardi G, Margineanu DG. Levetiracetam does not modulate neuronal voltage-gated Na+and T-type Ca2+currents. Seizure 2001, 10: 279–286.

    Article  CAS  PubMed  Google Scholar 

  58. Niespodziany I, Klitgaard H, Margineanu DG. Levetiracetam inhibits the high-voltage-activated Ca(2+) current in pyramidal neurones of rat hippocampal slices. Neurosci Lett 2001, 306: 5–8.

    Article  CAS  PubMed  Google Scholar 

  59. Pisani A, Bonsi P, Martella G, De Persis C, Costa C, Pisani F, et al. Intracellular calcium increase in epileptiform activity: Modulation by levetiracetam and lamotrigine. Epilepsia 2004, 45: 719–728.

    Article  CAS  PubMed  Google Scholar 

  60. Madeja M, Margineanu DG, Gorji A, Siep E, Boerrigter P, Klitgaard H, et al. Reduction of voltage-operated potassium currents by levetiracetam: A novel antiepileptic mechanism of action? Neuropharmacology 2003, 45: 661–671.

    Article  CAS  PubMed  Google Scholar 

  61. Carunchio I, Pieri M, Ciotti MT, Albo F, Zona C. Modulation of AMPA receptors in cultured cortical neurons induced by the antiepileptic drug levetiracetam. Epilepsia 2007, 48: 654–662.

    Article  CAS  PubMed  Google Scholar 

  62. Rigo JM, Hans G, Nguyen L, Rocher V, Belachew S, Malgrange B, et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol 2002, 136: 659–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Noyer M, Gillard M, Matagne A, Hénichart JP, Wülfert E. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. Eur J Pharmacol 1995, 286: 137–146.

    Article  CAS  PubMed  Google Scholar 

  64. Kaminski RM, Gillard M, Klitgaard H. Targeting SV2A for discovery of antiepileptic drugs. Jasper's Basic Mechanisms of the Epilepsies. Oxford University Press, 2012: 974–983.

  65. Meehan AL, Yang X, McAdams BD, Yuan L, Rothman SM. A new mechanism for antiepileptic drug action: Vesicular entry may mediate the effects of levetiracetam. J Neurophysiol 2011, 106: 1227–1239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yang XF, Weisenfeld A, Rothman SM. Prolonged exposure to levetiracetam reveals a presynaptic effect on neurotransmission. Epilepsia 2007, 48: 1861–1869.

    Article  CAS  PubMed  Google Scholar 

  67. Yang XF, Rothman SM. Levetiracetam has a time- and stimulation-dependent effect on synaptic transmission. Seizure 2009, 18: 615–619.

    Article  PubMed  Google Scholar 

  68. García-Pérez E, Mahfooz K, Covita J, Zandueta A, Wesseling JF. Levetiracetam accelerates the onset of supply rate depression in synaptic vesicle trafficking. Epilepsia 2015, 56: 535–545.

    Article  PubMed  Google Scholar 

  69. Gower AJ, 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 1995, 22: 207–213.

    Article  CAS  PubMed  Google Scholar 

  70. Loscher W, Schmidt D. Strategies in antiepileptic drug development: Is rational drug design superior to random screening and structural variation? Epilepsy Res 1994, 17: 95–134.

    Article  CAS  PubMed  Google Scholar 

  71. Loscher W, Honack D. Profile of ucb L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. Eur J Pharmacol 1993, 232: 147–158.

    Article  CAS  PubMed  Google Scholar 

  72. Löscher W, Reissmüller E, Ebert U. Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats. Epilepsy Res 2000, 40: 63–77.

    Article  PubMed  Google Scholar 

  73. Barton ME, Klein BD, Wolf HH, White HS. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res 2001, 47: 217–227.

    Article  CAS  PubMed  Google Scholar 

  74. Löscher W, Hönack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther 1998, 284: 474–479.

    PubMed  Google Scholar 

  75. Vinogradova LV, van Rijn CM. Anticonvulsive and antiepileptogenic effects of levetiracetam in the audiogenic kindling model. Epilepsia 2008, 49: 1160–1168.

    Article  CAS  PubMed  Google Scholar 

  76. Margineanu DG, Matagne A, Kaminski RM, Klitgaard H. Effects of chronic treatment with levetiracetam on hippocampal field responses after pilocarpine-induced status epilepticus in rats. Brain Res Bull 2008, 77: 282–285.

    Article  CAS  PubMed  Google Scholar 

  77. Sugaya Y, Maru E, Kudo K, Shibasaki T, Kato N. Levetiracetam suppresses development of spontaneous EEG seizures and aberrant neurogenesis following kainate-induced status epilepticus. Brain Res 2010, 1352: 187–199.

    Article  CAS  PubMed  Google Scholar 

  78. Yan HD, Cai JQ, Ishihara K, Nagayama T, Serikawa T, Sasa M. Separation of antiepileptogenic and antiseizure effects of levetiracetam in the spontaneously epileptic rat (SER). Epilepsia 2005, 46: 1170–1177.

    Article  CAS  PubMed  Google Scholar 

  79. Hovinga CA. Levetiracetam: A novel antiepileptic drug. Pharmacotherapy 2001, 21: 1375–1388.

    Article  CAS  PubMed  Google Scholar 

  80. De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: Part II, the clinical profile of a novel anticonvulsant drug. CNS Drug Rev 2007, 13: 57–78.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: A multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia 2000, 41: 1276–1283.

    Article  CAS  PubMed  Google Scholar 

  82. Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: Results of a double-blind, randomized clinical trial. Neurology 2000, 55: 236–242.

    Article  CAS  PubMed  Google Scholar 

  83. Shorvon SD, Löwenthal A, Janz D, Bielen E, Loiseau P. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000, 41: 1179–1186.

    Article  CAS  PubMed  Google Scholar 

  84. Wu XY, Hong Z, Wu X, Wu LW, Wang XF, Zhou D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in Chinese patients with refractory partial-onset seizures. Epilepsia 2009, 50: 398–405.

    Article  CAS  PubMed  Google Scholar 

  85. Piña-Garza JE, Nordli DR Jr, Rating D, Yang H, Schiemann-Delgado J, Duncan B, et al. Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures. Epilepsia 2009, 50: 1141–1149.

    Article  PubMed  Google Scholar 

  86. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007, 68: 402–408.

    Article  CAS  PubMed  Google Scholar 

  87. Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado J, et al. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology 2008, 70: 607–616.

    Article  CAS  PubMed  Google Scholar 

  88. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U, Group LNS. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 2007, 69: 1751–1760.

    Article  CAS  PubMed  Google Scholar 

  89. Strzelczyk A, Schubert-Bast S. A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication. CNS Drugs 2022, 36: 217–237.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Dewolfe JL, Szaflarski JP. Levetiracetam use in the critical care setting. Front Neurol 2013, 4: 121.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Fang T, Valdes E, Frontera JA. Levetiracetam for seizure prophylaxis in neurocritical care: A systematic review and meta-analysis. Neurocrit Care 2022, 36: 248–258.

    Article  PubMed  Google Scholar 

  92. Howard P, Remi J, Remi C, Charlesworth S, Whalley H, Bhatia R, et al. Levetiracetam. J Pain Symptom Manag 2018, 56: 645–649.

    Article  Google Scholar 

  93. Patsalos PN. Pharmacokinetic profile of levetiracetam: Toward ideal characteristics. Pharmacol Ther 2000, 85: 77–85.

    Article  CAS  PubMed  Google Scholar 

  94. Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs. Focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996, 31: 29–46.

    Article  CAS  PubMed  Google Scholar 

  95. Hu Q, Zhang F, Teng W, Hao F, Zhang J, Yin M, et al. Efficacy and safety of antiepileptic drugs for refractory partial-onset epilepsy: A network meta-analysis. J Neurol 2018, 265: 1–11.

    Article  PubMed  Google Scholar 

  96. Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006, 66: 1654–1660.

    Article  CAS  PubMed  Google Scholar 

  97. Steinhoff BJ, Somerville ER, Van Paesschen W, Ryvlin P, Schelstraete I. The SKATE study: An open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy. Epilepsy Res 2007, 76: 6–14.

    Article  CAS  PubMed  Google Scholar 

  98. Morrell MJ, Leppik I, French J, Ferrendelli J, Han J, Magnus L. The KEEPER trial: Levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res 2003, 54: 153–161.

    Article  CAS  PubMed  Google Scholar 

  99. Kwan P, Lim SH, Chinvarun Y, Cabral-Lim L, Aziz ZA, Lo YK, et al. Efficacy and safety of levetiracetam as adjunctive therapy in adult patients with uncontrolled partial epilepsy: The Asia SKATE II Study. Epilepsy Behav 2010, 18: 100–105.

    Article  PubMed  Google Scholar 

  100. Lyseng-Williamson KA. Levetiracetam: A review of its use in epilepsy. Drugs 2011, 71: 489–514.

    CAS  PubMed  Google Scholar 

  101. Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H. Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. Br J Pharmacol 2008, 154: 1662–1671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Klitgaard H, Matagne A, Nicolas JM, Gillard M, Lamberty Y, De Ryck M, et al. Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia 2016, 57: 538–548.

    Article  PubMed  Google Scholar 

  103. Klitgaard H, Matagne A. Mechanisms of action of levetiracetam and newer SV2A ligands. Chapter 3, Blue Books of Neurology 2009, 33: 27–38.

  104. Stephen LJ, Brodie MJ. Brivaracetam: A novel antiepileptic drug for focal-onset seizures. Ther Adv Neurol Disord 2017, 11: 1756285617742081.

    PubMed  PubMed Central  Google Scholar 

  105. Gillard M, Fuks B, Leclercq K, Matagne A. Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: Relationship to anti-convulsant properties. Eur J Pharmacol 2011, 664: 36–44.

    Article  CAS  PubMed  Google Scholar 

  106. Yang X, Bognar J Jr, He T, Mohammed M, Niespodziany I, Wolff C, et al. Brivaracetam augments short-term depression and slows vesicle recycling. Epilepsia 2015, 56: 1899–1909.

    Article  CAS  PubMed  Google Scholar 

  107. Zona C, Pieri M, Carunchio I, Curcio L, Klitgaard H, Margineanu DG. Brivaracetam (ucb 34714) inhibits Na+ current in rat cortical neurons in culture. Epilepsy Res 2010, 88: 46–54.

    Article  CAS  PubMed  Google Scholar 

  108. Niespodziany I, André VM, Leclère N, Hanon E, Ghisdal P, Wolff C. Brivaracetam differentially affects voltage-gated sodium currents without impairing sustained repetitive firing in neurons. CNS Neurosci Ther 2015, 21: 241–251.

    Article  CAS  PubMed  Google Scholar 

  109. Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic vesicle glycoprotein 2A ligands in the treatment of epilepsy and beyond. CNS Drugs 2016, 30: 1055–1077.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Tai KK, Truong DD. Brivaracetam is superior to levetiracetam in a rat model of post-hypoxic myoclonus. J Neural Transm 2007, 114: 1547–1551.

    Article  CAS  PubMed  Google Scholar 

  111. Niquet J, Suchomelova L, Thompson K, Klitgaard H, Matagne A, Wasterlain C. Acute and long-term effects of brivaracetam and brivaracetam-diazepam combinations in an experimental model of status epilepticus. Epilepsia 2017, 58: 1199–1207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tulli E, Di Cara G, Iapadre G, Striano P, Verrotti A. An update on brivaracetam for the treatment of pediatric partial epilepsy. Expert Opin Pharmacother 2021, 22: 1387–1395.

    Article  CAS  PubMed  Google Scholar 

  113. Van Paesschen W, Hirsch E, Johnson M, Falter U, von Rosenstiel P. Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial-onset seizures: A phase IIb, randomized, controlled trial. Epilepsia 2013, 54: 89–97.

    Article  PubMed  Google Scholar 

  114. Biton V, Berkovic SF, Abou-Khalil B, Sperling MR, Johnson ME, Lu S. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: A phase III randomized, double-blind, placebo-controlled trial. Epilepsia 2014, 55: 57–66.

    Article  CAS  PubMed  Google Scholar 

  115. Kwan P, Trinka E, Van Paesschen W, Rektor I, Johnson ME, Lu S. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia 2014, 55: 38–46.

    Article  CAS  PubMed  Google Scholar 

  116. Klein P, Schiemann J, Sperling MR, Whitesides J, Liang W, Stalvey T, et al. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia 2015, 56: 1890–1898.

    Article  CAS  PubMed  Google Scholar 

  117. Liu E, Dilley D, McDonough B, Stockis A, Daniels T. Safety and tolerability of adjunctive brivaracetam in pediatric patients < 16 years with epilepsy: An open-label trial. Paediatr Drugs 2019, 21: 291–301.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Nissenkorn A, Tzadok M, Bar-Yosef O, Ben-Zeev B. Treatment with brivaracetam in children - The experience of a pediatric epilepsy center. Epilepsy Behav 2019, 101: 106541.

    Article  PubMed  Google Scholar 

  119. Visa-Reñé N, Raspall-Chaure M, Paredes-Carmona F, Coromina JS, Macaya-Ruiz A. Clinical experience with brivaracetam in a series of 46 children. Epilepsy Behav 2020, 107: 107067.

    Article  PubMed  Google Scholar 

  120. McGuire S, Silva G, Lal D, Khurana DS, Legido A, Hasbani D, et al. Safety and efficacy of brivaracetam in pediatric refractory epilepsy: A single-center clinical experience. J Child Neurol 2020, 35: 102–105.

    Article  PubMed  Google Scholar 

  121. Kälviäinen R, Genton P, Andermann E, Andermann F, Magaudda A, Frucht SJ, et al. Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies. Epilepsia 2016, 57: 210–221.

    Article  PubMed  Google Scholar 

  122. Rolan P, Sargentini-Maier ML, Pigeolet E, Stockis A. The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men. Br J Clin Pharmacol 2008, 66: 71–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Stockis A, Sargentini-Maier ML, Horsmans Y. Brivaracetam disposition in mild to severe hepatic impairment. J Clin Pharmacol 2013, 53: 633–641.

    Article  CAS  PubMed  Google Scholar 

  124. Sargentini-Maier ML, Sokalski A, Boulanger P, Jacobs T, Stockis A. Brivaracetam disposition in renal impairment. J Clin Pharmacol 2012, 52: 1927–1933.

    Article  CAS  PubMed  Google Scholar 

  125. Coppola G, Iapadre G, Operto FF, Verrotti A. New developments in the management of partial-onset epilepsy: Role of brivaracetam. Drug Des Devel Ther 2017, 11: 643–657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nicolas JM, Hannestad J, Holden D, Kervyn S, Nabulsi N, Tytgat D, et al. Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action. Epilepsia 2016, 57: 201–209.

    Article  CAS  PubMed  Google Scholar 

  127. Sargentini-Maier ML, Espié P, Coquette A, Stockis A. Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects. Drug Metab Dispos 2008, 36: 36–45.

    Article  CAS  PubMed  Google Scholar 

  128. Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results from a double-blind, randomized, placebo-controlled trial. Epilepsia 2014, 55: 47–56.

    Article  CAS  PubMed  Google Scholar 

  129. Leclercq K, Matagne A, Provins L, Klitgaard H, Kaminski RM. Pharmacological profile of the novel antiepileptic drug candidate padsevonil: Characterization in rodent seizure and epilepsy models. J Pharmacol Exp Ther 2020, 372: 11–20.

    Article  CAS  PubMed  Google Scholar 

  130. Wood M, Daniels V, Provins L, Wolff C, Kaminski RM, Gillard M. Pharmacological profile of the novel antiepileptic drug candidate padsevonil: Interactions with synaptic vesicle 2 proteins and the GABAA receptor. J Pharmacol Exp Ther 2020, 372: 1–10.

    Article  CAS  PubMed  Google Scholar 

  131. Niespodziany I, Ghisdal P, Mullier B, Wood M, Provins L, Kaminski RM, et al. Functional characterization of the antiepileptic drug candidate, padsevonil, on GABAA receptors. Epilepsia 2020, 61: 914–923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Rundfeldt C, Wlaź P, Hönack D, Löscher W. Anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. Comparison of diazepam, bretazenil and abecarnil. J Pharmacol Exp Ther 1995, 275: 693–702.

    CAS  PubMed  Google Scholar 

  133. Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: A future for subtype-selective GABA(A) receptor modulators? Adv Pharmacol Sci 2012, 2012: 416864.

    PubMed  PubMed Central  Google Scholar 

  134. Gravielle MC. Activation-induced regulation of GABAA receptors: Is there a link with the molecular basis of benzodiazepine tolerance? Pharmacol Res 2016, 109: 92–100.

    Article  CAS  PubMed  Google Scholar 

  135. Kaminski RM, Fu Z, Venkatesan K, Mazzuferi M, Leclercq K, Seutin V, et al. 11-Deoxycortisol impedes GABAergic neurotransmission and induces drug-resistant status epilepticus in mice. Neuropharmacology 2011, 60: 1098–1108.

    Article  CAS  PubMed  Google Scholar 

  136. Muglia P, Hannestad J, Brandt C, DeBruyn S, Germani M, Lacroix B, et al. Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: A translational approach. Brain Commun 2020, 2: fcaa183.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E, Tomson T, et al. Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development. Epilepsia 2018, 59: 1842–1866.

    Article  PubMed  Google Scholar 

  138. Johannessen Landmark C, Johannessen SI. Pharmacological management of epilepsy: Recent advances and future prospects. Drugs 2008, 68: 1925–1939.

    Article  PubMed  Google Scholar 

  139. Klein P, Diaz A, Gasalla T, Whitesides J. A review of the pharmacology and clinical efficacy of brivaracetam. Clin Pharmacol 2018, 10: 1–22.

    PubMed  PubMed Central  Google Scholar 

  140. Feyissa AM. Brivaracetam in the treatment of epilepsy: A review of clinical trial data. Neuropsychiatr Dis Treat 2019, 15: 2587–2600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hajduk PJ, Greer J. A decade of fragment-based drug design: Strategic advances and lessons learned. Nat Rev Drug Discov 2007, 6: 211–219.

    Article  CAS  PubMed  Google Scholar 

  142. Fattori D, Squarcia A, Bartoli S. Fragment-based approach to drug lead discovery: Overview and advances in various techniques. Drugs R D 2008, 9: 217–227.

    Article  CAS  PubMed  Google Scholar 

  143. Klitgaard H. Levetiracetam: The preclinical profile of a new class of antiepileptic drugs? Epilepsia 2001, 42: 13–18.

    Article  PubMed  Google Scholar 

  144. Rogawski MA. Brivaracetam: A rational drug discovery success story. Br J Pharmacol 2008, 154: 1555–1557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Malawska B, Kulig K. Brivaracetam: A new drug in development for epilepsy and neuropathic pain. Expert Opin Investig Drugs 2008, 17: 361–369.

    Article  CAS  PubMed  Google Scholar 

  146. Pollard JR. Seletracetam, a small molecule SV2A modulator for the treatment of epilepsy. Curr Opin Investig Drugs 2008, 9: 101–107.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This review was supported by funding from the High-level New R&D Institute (2019B090904008) and the High-level Innovative Research Institute (2021B0909050003) of the Department of Science and Technology of Guangdong Province, National Science and Technology Innovation 2030 Major Program (2021ZD0200900), Shanghai Municipal Science and Technology Major Project (2018SHZDZX05), Zhongshan Municipal Bureau of Science and Technology (CXTD2022013) and the National Science Fund for Distinguished Young Scholars (81825021) and the funding from Zhongshan Municipal Bureau of Science and Technology (210724194041939).

Author information

Author notes

  1. Peng-Peng Wu, Bi-Rong Cao and Fu-Yun Tian contributed equally to this review.

Authors and Affiliations

  1. Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Peng-Peng Wu, Bi-Rong Cao, Fu-Yun Tian & Zhao-Bing Gao

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Peng-Peng Wu, Bi-Rong Cao & Zhao-Bing Gao

  3. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China

    Fu-Yun Tian & Zhao-Bing Gao

Authors
  1. Peng-Peng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bi-Rong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fu-Yun Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhao-Bing Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Fu-Yun Tian or Zhao-Bing Gao.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, PP., Cao, BR., Tian, FY. et al. Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil. Neurosci. Bull. (2023). https://doi.org/10.1007/s12264-023-01138-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12264-023-01138-2

Keywords

Search

Navigation