Levetiracetam – a drug that can be used not only in the treatment of epilepsy

REVIEW ARTICLE

Levetiracetam – a drug that can be used not only in the treatment of epilepsy

Bogusława Pietrzak 1 , Alicja Natanek 1 , Ewa Zwierzyńska 1

1. Zakład Farmakodynamiki Katedry Biofarmacji Uniwersytetu Medycznego w Łodzi,

Published: 2019-09-17
DOI: 10.5604/01.3001.0013.4670
GICID: 01.3001.0013.4670
Available language versions: en pl
Issue: Postepy Hig Med Dosw 2019; 73 : 457-466

 

Abstract

Levetiracetam, which belongs to the new generation of antiepileptic drugs, has a unique and not well-known mechanism of action. The drug affects the release of neurotransmitters through the binding to the synaptic vesicle protein SV2A. Moreover, it acts on calcium channels, inhibits glutamatergic neurotransmission and affects GABA-ergic neurotransmission through e.g. the Zn²⁺-induced suppression of GABAA-mediated presynaptic inhibition and the modulation of the action of GABAA antagonists. Levetiracetam has also neuroprotective activity which is associated with the influence on transcription processes, neurotransmission, antioxidant and anti-inflammatory activity. The results of recent research indicate that this complex action creates the prospect of using it in the alleviation of epileptogenesis, poststroke seizuires, seizure prophylaxis in brain injured patients and diabetic neuropathy. Furthermore, the drug may also have a beneficial effect in the treatment of Alzheimer patients with epileptic seizures and levodopa-induced dyskinesias in Parkinson’s disease.

References

  • 1. Bajjalieh S.M., Frantz G.D., Weimann J.M., McConnell S.K., SchellerR.H.: Differential expression of synaptic vesicle protein 2 (SV2)isoforms. J. Neurosci., 1994; 14: 5223–5235
    Google Scholar
  • 2. Belcastro V., Costa C., Galletti F., Pisani F., Calabresi P., Parnetti L.: Levetiracetammonotherapy in Alzheimer patients with late-onset seizures:a prospective observational study. Eur. J. Neurol., 2007; 14: 1176–1178
    Google Scholar
  • 3. Catterall W.A.: Voltage-gated calcium channels. Cold Spring Harb.Perspect. Biol., 2011; 3: a003947
    Google Scholar
  • 4. Chaari A., Mohamed A.S., Abdelhakim K., Kauts V., Casey W.F.:Levetiracetam versus phenytoin for seizure prophylaxis in brain injured patients: a systematic review and meta-analysis. Int. J. Clin. Pharm., 2017; 39: 998–1003
    Google Scholar
  • 5. Chen Y.H., Kuo T.T., Yi-Kung Huang E., Hoffer B.J., Chou Y.C.,Chiang Y.H., Ma H.I., Miller J.P.: Profound deficits in hippocampalsynaptic plasticity after traumatic brain injury and seizure is amelioratedby prophylactic levetiracetam. Oncotarget, 2018; 9: 11515–11527
    Google Scholar
  • 6. Christensen K.V., Leffers H., Watson W.P., Sánchez C., Kallunki P., Egebjerg J.: Levetiracetam attenuates hippocampal expression of synaptic plasticity-related immediateearly and late response genes in amygdala-kindled rats. BMC Neurosci., 2010; 11: 9
    Google Scholar
  • 7. Consoli D., Bosco D., Postorino P., Galati F., Plastino M., PerticoniG.F., Ottonello G.A., Passarella B., Ricci S., Neri G., Toni D., EPIC Study:Levetiracetam versus carbamazepine in patients with late poststrokeseizures: a multicenter prospective randomized open-label study(EpIC Project). Cerebrovasc. Dis., 2012; 34: 282–289
    Google Scholar
  • 8. Crowder K.M., Gunther J.M., Jones T.A., Hale B.D, Zhang H.Z., PetersonM.R., Scheller R.H., Chavkin C., Bajjalieh S.M.: Abnormal neurotransmissionin mice lacking synaptic vesicle protein 2A (SV2A).Proc. Natl. Acad. Sci. USA, 1999; 96: 15268–15273
    Google Scholar
  • 9. Cumbo E., Ligori L.D.: Levetiracetam, lamotrigine, and phenobarbitalin patients with epileptic seizures and Alzheimer’s disease.Epilepsy Behav., 2010; 17: 461–466
    Google Scholar
  • 10. DeLorenzo R.J., Sun D.A., Deshpande L.S.: Cellular mechanisms underlyingacquired epilepsy: The calcium hypothesis of the inductionand maintainance of epilepsy. Pharmacol. Ther., 2005; 105: 229–266
    Google Scholar
  • 11. De Ruijter A.J., Van Gennip A.H., Caron H.N., Kemp S., Van KuilenburgA.B.: Histone deacetylases (HDACs): characterization of theclassical HDAC family. Biochem. J., 2003; 370: 737–749
    Google Scholar
  • 12. Dircio-Bautista M., Colín-González A.L., Aguilera G., Maya-LópezM., Villeda-Hernández J., Galván-Arzate S., García E., Túnez I.,Santamaría A.: The antiepileptic drug levetiracetam protects againstquinolinic acid-induced toxicity in the rat striatum. Neurotox.Res., 2018; 33: 837–845
    Google Scholar
  • 13. Erbas O., Oltulu F., Yilmaz M., Yavasoglu A., Taskiran D.: Neuroprotectiveeffects of chronic administration of levetiracetam in a rat modelof diabetic neuropathy. Diabetes Res. Clin. Pract., 2016; 114: 106–116
    Google Scholar
  • 14. Erbaş O., Yılmaz M., Taşkıran D.: Levetiracetam attenuates rotenone-induced toxicity: A rat model of Parkinson’s disease. Environ.Toxicol. Pharmacol., 2016; 42: 226–230
    Google Scholar
  • 15. Eriksson C., Van Dam A.M., Lucassen P.J., Bol J.G., Winblad B.,Schultzberg M.: Immunohistochemical localization of interleukin-1β, interleukin-1 receptor antagonist and interleukin-1β convertingenzyme/caspase-1 in the rat brain after peripheral administrationof kainic acid. Neuroscience, 1999; 93: 915–930
    Google Scholar
  • 16. Eyal S., Yagen B., Sobol E., Altschuler Y., Shmuel M., Bialer M.:The activity of antiepileptic drugs as histone deacetylase inhibitors.Epilepsia, 2004; 45: 737–744
    Google Scholar
  • 17. Fukuyama K., Tanahashi S., Nakagawa M., Yamamura S., MotomuraE., Shiroyama T., Tanii H., Okada M.: Levetiracetam inhibitsneurotransmitter release associated with CICR. Neurosci. Lett.,2012; 518: 69–74
    Google Scholar
  • 18. Greenwood S.M., Connolly C.N.: Dendritic and mitochondrialchanges during glutamate excitotoxicity. Neuropharmacology,2007; 53: 891–898
    Google Scholar
  • 19. Huang L., Li Q., Wen R., Yu Z., Li N., Ma L., Feng W.: Rho-kinaseinhibitor prevents acute injury against transient focal cerebral ischemiaby enhancing the expression and function of GABA receptorsin rats. Eur. J. Pharmacol., 2017; 797: 134–142
    Google Scholar
  • 20. Janz R., Goda Y., Geppert M., Missler M., Südhof T.C.: SV2A andSV2B function as redundant Ca2+ regulators in neurotransmitterrelease. Neuron, 1999; 24: 1003–1016
    Google Scholar
  • 21. Ji-qun C., Ishihara K., Nagayama T., Serikawa T., Sasa M.: Long-lasting antiepileptic effects of levetiracetam against epileptic seizuresin the spontaneously epileptic rat (SER): differentiation oflevetiracetam from conventional antiepileptic drugs. Epilepsia, 2005;46: 1362–1370
    Google Scholar
  • 22. Kutlu G., Gomceli Y.B., Unal Y., Inan L.E.: Levetiracetam monotherapyfor late poststroke seizures in the elderly. Epilepsy Behav.,2008; 13: 542–544
    Google Scholar
  • 23. Lee C.Y., Chen C.C., Liou H.H.: Levetiracetam inhibits glutamatetransmission through presynaptic P/Q-type calcium channelson the granule cells of the dentate gyrus. Br. J. Pharmacol., 2009;158: 1753–1762
    Google Scholar
  • 24. Löscher W., Hönack D., Bloms-Funke P.: The novel antiepilepticdrug levetiracetam (ucb L059) induces alterations in GABA metabolismand turnover in discrete areas of rat brain and reduceyansneuronal activity in substantia nigra pars reticulata. Brain Res.,1996; 735: 208–216
    Google Scholar
  • 25. Lukyanetz E.A., Shkryl V.M., Kostyuk P.G.: Selective blocked ofN-type calcium channels by levetiracetam. Epilepsia, 2002; 43: 9–18
    Google Scholar
  • 26. Lynch B.A., Lambeng N., Nocka K., Kensel-Hammes P., BajjaliehS.M., Matagne A., Fuks B.: The synaptic vesicle protein SV2A is thebinding site for the antiepileptic drug levetiracetam. Proc. Natl.Acad. Sci. USA, 2004; 101: 9861–9866
    Google Scholar
  • 27. Lyons K.E., Pahwa R.: Efficacy and tolerability of levetiracetamin Parkinson disease patients with levodopa-induced dyskinesia.Clin. Neuropharmacol., 2006; 29: 148–153
    Google Scholar
  • 28. Madeja M., Margineanu D.G., Gorji A., Siep E., Boerrigter P., KlitgaardH., Speckmann E.J.: Reduction of voltage-operated potassiumcurrents by levetiracetam: a novel antiepileptic mechanism of action.Neuropharmacology, 2003; 45: 661–671
    Google Scholar
  • 29. Margineanu D.G., Matagne A., Kaminski R.M., Klitgaard H.: Effectsof chronic treatment with levetiracetam on hippocampal fieldresponses after pilocarpine-induced status epilepticus in rats. BrainRes. Bull., 2008; 77: 282–285
    Google Scholar
  • 30. Marini H., Costa C., Passaniti M., Esposito M., Campo G.M., IentileR., Adamo E.B., Marini R., Calabresi P., Altavilla D., Minutoli L., PisaniF., Squadrito F.: Levetiracetam protects against kainic acid-inducedtoxicity. Life Sci., 2004; 74: 1253–1264
    Google Scholar
  • 31. Matveeva E.A., Vanaman T.C., Whiteheart S.W., Slevin J.T.: Levetiracetamprevents kindling-induced asymmetric accumulationof hippocampal 7S SNARE complexes. Epilepsia, 2008; 49: 1749–1758
    Google Scholar
  • 32. Micov A., Tomić M., Pecikoza U., Ugrešić N., Stepanović-PetrovićR.: Levetiracetam synergises with common analgesics in producingantinociception in a mouse model of painful diabetic neuropathy.Pharmacol. Res., 2015; 97: 131–142
    Google Scholar
  • 33. Micov A, Tomić M, Popović B, Stepanović-Petrović R.: The antihyperalgesiceffect of levetiracetam in an inflammatory modelof pain in rats: mechanism of action. Br. J. Pharmacol., 2010; 161:384–392
    Google Scholar
  • 34. Miyazaki I., Murakami S., Torigoe N., Kitamura Y., Asanuma M.:Neuroprotective effects of levetiracetam target xCT in astrocytes inParkinsonian mice. J. Neurochem., 2016; 136: 194–204
    Google Scholar
  • 35. Nagarkatti N., Deshpande L.S., Carter D.S., DeLorenzo R.J.: Dantroleneinhibits the calcium plateau and prevents the developmentof spontaneous recurrent epileptiform discharges following in vitrostatus epilepticus. Eur. J. Neurosci., 2010; 32: 80–88
    Google Scholar
  • 36. Nagarkatti N., Deshpande L.S., DeLorenzo R.J.: Levetiracetaminhibits both ryanodine and IP3 receptor activated calcium inducedcalcium release in hippocampal neurons in culture. Neurosci.Lett., 2008; 436: 289–293
    Google Scholar
  • 37. Ohno Y., Ishihara S., Terada R., Serikawa T., Sasa M.: Antiepileptogenicand anticonvulsive actions of levetiracetam in a pentylenetetrazolekindling model. Epilepsy Res., 2010; 89: 360-364
    Google Scholar
  • 38. Poulain P., Margineanu D.G.: Levetiracetam opposes the actionof GABAA antagonists in hypothalamic neurons. Neuropharmacology,2002; 42: 346–352
    Google Scholar
  • 39. Pyle R.A., Schivell A.E., Hidaka H., Bajjalieh S.M.: Phosphorylationof synaptic vesicle protein 2 modulates binding to synaptotagmin.J. Biol. Chem., 2000; 275: 17195–17200
    Google Scholar
  • 40. Qiu X., Xiao X., Li N., Li Y.: Histone deacetylases inhibitors (HDACis)as novel therapeutic application in various clinical diseases.Prog. Neuropsychopharmacol. Biol. Psychiatry, 2017; 72: 60–72
    Google Scholar
  • 41. Salińska E., Łazarewicz J.W.: Rola wapnia w fizjologii i patologiineuronów. Postępy Biochem., 2012; 58: 403–417
    Google Scholar
  • 42. Shi J.Q., Wang B.R., Tian Y.Y., Xu J., Gao L., Zhao S.L., Jiang T.,Xie H.G., Zhang Y.D.: Antiepileptics topiramate and levetiracetamalleviate behavioral deficits and reduce neuropathology in APPswe/PS1dE9 transgenic mice. CNS Neurosci. Ther., 2013; 19: 871–881
    Google Scholar
  • 43. Stathis P., Konitsiotis S., Tagaris G., Peterson D., VALID-PDStudyGroup: Levetiracetam for the management of levodopa–induced dyskinesias in Parkinson’s disease. Mov. Disord., 2011;26: 264–270
    Google Scholar
  • 44. Stepanović-Petrović R.M., Micov A.M., Tomić M.A., Ugrešić N.D.:The local peripheral antihyperalgesic effect of levetiracetam andits mechanism of action in an inflammatory pain model. Anesth.Analg., 2012; 115: 1457–1466
    Google Scholar
  • 45. Sugata S., Hanaya R., Kumafuji K., Tokudome M., Serikawa T.,Kurisu K., Arita K., Sasa M.: Neuroprotective effect of levetiracetamon hippocampal sclerosis-like change in spontaneously epilepticrats. Brain Res. Bull., 2011; 86: 36–41
    Google Scholar
  • 46. Thöne J., Ellrichmann G., Faustmann P.M., Gold R., Haghikia A.:Anti-inflammatory effects of levetiracetam in experimental autoimmuneencephalomyelitis. Int. Immunopharmacol., 2012; 14: 9–12
    Google Scholar
  • 47. Ueda Y., Doi T., Nagatomo K., Tokumaru J., Takaki M., WillmoreL.J.: Effect of levetiracetam on molecular regulation of hippocampalglutamate and GABA transporters in rats with chronicseizures induced by amygdalar FeCl3 injection. Brain Res., 2007;1151: 55–61
    Google Scholar
  • 48. Vinogradova L.V., van Rijn C.M.: Anticonvulsive and antiepileptogeniceffects of levetiracetam in the audiogenic kindling model.Epilepsia, 2008; 49: 1160–1168
    Google Scholar
  • 49. Wakita M., Kotani N., Kogure K., Akaike N.: Inhibition of excitatorysynaptic transmission in hippocampal neurons by levetiracetaminvolves Zn2+-dependent GABA type A receptor-mediatedpresynaptic modulation. J. Pharmacol. Exp. Ther., 2014; 348: 246-259
    Google Scholar
  • 50. Wang H., Gao J., Lassiter T.F., McDonagh D.L., Sheng H., WarnerD.S., Lynch J.R., Laskowitz D.T.: Levetiracetam is neuroprotective inmurine models of closed head injury and subarachnoid hemorrhage.Neurocrit. Care, 2006; 5: 71-78
    Google Scholar
  • 51. Wolz M., Löhle M., Strecker K., Schwanebeck U., Schneider C., ReichmannH., Grählert X., Schwarz J., Storch A.: Levetiracetam for levodopa-induced dyskinesia in Parkinson’s disease: a randomized, double–blind, placebo-controlled trial. J. Neural Transm., 2010; 117: 1279-1286
    Google Scholar
  • 52. Wong K.K., Alty J.E., Goy A.G., Raghav S., Reutens D.C., Kempster P.A.:A randomized, double-blind, placebo-controlled trial of levetiracetamfor dyskinesia in Parkinson’s disease. Mov. Disord., 2011; 26: 1552-1555
    Google Scholar
  • 53. Yan H.D., Ishihara K., Seki T., Hanaya R., Kurisu K., Arita K., SerikawaT., Sasa M.: Inhibitory effects of levetiracetam on the high-voltage-activated L-type Ca2+ channels in hippocampal CA3 neurons ofspontaneously epileptic rat (SER). Brain Res. Bull., 2013; 90: 142-148
    Google Scholar
  • 54. Yan H.D., Ji-qun C., Ishihara K., Nagayama T., Serikawa T., Sasa M.:Separation of antiepileptogenic and antiseizure effects of levetiracetamin the spontaneously epileptic rat (SER). Epilepsia, 2005; 46: 1170-1177
    Google Scholar

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