Mini rev he en Pi Anna nivers vised d for e use mia is receiving increasing attention and the antiepileptic drug levetiracetam, a 2S-(2-oxo-1-pyrrolidiny1) butanamide, belonging to neuroprotective functions [1,2]. Levetiracetam is sented by stroke [12]. Usually, elderly patients become On the basis of the similarity of the cascade of synap- tic and intracellular events exhibited by epilepsy and eurology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Address: Clinica Neurologica, Azienda Ospedaliera Sant’Anna, via Napoleona, 60-22100 Como, Italy. Tel.: +39 3485452889. E-mail address:
[email protected] (V. Belcastro). Brain & Development 33 (2 0387-7604/$ - see front matter � 2010 The Japanese Society of Child N approved as monotherapy in partial epilepsy with or without secondary generalization [3], and it maintains its efficacy and safety during long-term therapy [4].More- over, levetiracetam may be employed alone or in combi- nations with valproate, lamotrigine or phenobarbital in the treatment of idiopathic generalized epilepsies [5]. Furthermore, levetiracetam shows a particularly good balance between efficacy and tolerability, not only in the management of epilepsy but also in movement [6– 9] and mood disorders [10]. Interestingly, levetiracetam seizure free with relatively low doses of antiepileptic drugs (AEDs); nevertheless, comorbidities and comedi- cations frequently raise concerns about potentially detri- mental drug interactions [12]. Among the recently- introduced AEDs, levetiracetam exhibits favourable characteristics which make it an ideal candidate as a first-choice drug for post-stroke seizures. This review discusses the potential neuroprotective role in brain ischemia and the therapeutic implications of levetiracetam in post-stroke epilepsy. 2. Neuroprotection in brain ischemia: potential mechanisms of levetiracetam the pyrrolidone family, could have a crucial role in regulation of epileptogenesis and neuroprotection. Recent observations suggest that levetiracetam is both safe and effective against post-stroke seizures. In this review, the potential neuroprotective role in brain ischemia and the therapeutic implications of levetiracetam in post-stroke epilepsy are discussed. � 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Levetiracetam; Brain ischemia; Neuroprotection; Epileptogenesis; Post-stroke seizures 1. Introduction Levetiracetam is a 2S-(2-oxo-1-pyrrolidiny1) butana- mide, belonging to the pyrrolidone family, a class of drugs with a wide spectrum of actions, such as antiepileptic and might have a neuroprotective role against ischemic brain injury [11]. In the elderly, the incidence of new-onset epilepsy is higher than in any other age group and, in this frail pop- ulation, the most cause of symptomatic epilepsy is repre- Levetiracetam in brain isc in neuroprotection and prev Vincenzo Belcastro a,*, Laura aNeurology Clinic, S. bNeurology Clinic, U Received 5 February 2010; received in re Abstract Several new antiepileptic drugs (AEDs) have been introduce target multiple cellular sites both pre- and postsynaptically. Th doi:10.1016/j.braindev.2010.06.008 iew mia: Clinical implications tion of post-stroke epilepsy erguidi a, Nicola Tambasco b Hospital, Como, Italy ity of Perugia, Italy form 2 June 2010; accepted 4 June 2010 clinical use recently. These new AEDs, like the classic AEDs, of AEDs as a possible neuroprotective strategy in brain ische- www.elsevier.com/locate/braindev 011) 289–293 vascular brain injuries, AEDs have been tested as possi- ble neuroprotective agents in animal models of stroke [11]. Among the antiepileptic drugs, levetiracetam may have a crucial role in the regulation of epileptogenesis and neuroprotection [13]. Some particular mechanisms of action of levetiracetam might be involved in neuro- protection after vascular injury (Table 1). Experimental observations have demonstrated that levetiracetam has a direct ability to protect against the neurotoxicity induced by chemical compounds such as kainic acid [14]. Interestingly, levetiracetam’s neuroprotective proper- ties have been investigated in the rat middle cerebral artery (MCA) occlusion model, a condition of focal cere- bral ischemia [15]. In this study, application of levetirace- tam reduced the infarct volume without altered body temperature, with better results than those obtained by 290 V. Belcastro et al. / Brain & Devel application of a non-competitive N-methyl-D-aspartic acid (NMDA) antagonist [15]. The influx of calcium into cells triggers the cascade of events that brings about cell death, so it is possible that selective blockade of calcium channels may be neuro- protective. There are different classes of calcium chan- nels. N and P/Q subtypes in particular are involved in controlling the release of neurotransmitters, while L channels regulate signalling events at a postsynaptic level. It is likely that the selective modulation of N and P/Q subtypes could be effective as a neuroprotective strategy [11]. In this sense, levetiracetam could be con- sidered, because it regulates the influx of calcium into the cells [16–18], selectively blocking N-type [19], but not the T-type channel [20]. Moreover, there is evidence that levetiracetam reduces the flow of potassium within the cell [21]. In this way, levetiracetam modulates mem- brane depolarization and then interferes with the pro- cesses leading to irreversible cellular damage [21]. Furthermore, it has been demonstrated using experi- mental models that GABA neurotransmission is Table 1 Summary of the potential mechanisms of levetiracetam relevant to neuroprotection. Species Model Mechanism Reference Rat Kainic acid Inhibition of lipid peroxidation [14] Rat Hippocampal neurons in culture Inhibition of Ca release [16,17] Rat Hippocampal CA1 neurons Reduction of potassium currents [21] Rat Striatal neurons Alterations in GABA metabolism and turnover [24] Rat MCA occlusion NA [15] HeLa cells Inhibition of histone deacetylases [34] MCA, middle cerebral artery; NA, not available. Note: HeLa cell is an immortal cell line derived from cervical cancer cells taken from a patient named Henrietta Lacks. strongly depressed during brain ischemia [11]. Therefore all pre- and postsynaptic strategies supporting and increasing GABAergic levels could exerts a neuroprotec- tive effect [22]. Although levetiracetam does not directly modulate the GABAergic system [23], it could interfere with GABA turnover [24] and with the action of GABA- A antagonists [25], as possible further mechanisms of the neuroprotective effect [26]. Negative regulation of excitatory transmission can be considered a prominent protection strategy against ischemia [27]. Modulation of ionotropic and metabotro- pic (group I) glutamatergic receptors has to be consid- ered the main mechanism of neuroprotection. There is no evidence of a direct interaction between levetiracetam with glutamate receptors, but a role could be postulated in negative modulation of excitatory transmission, through a specific link to a site in the central nervous system membranes [28]. In particular, it has been dem- onstrated that levetiracetam binds to a synaptic vesicle protein called SV2A [29]. This is the most expressed type of a family of integral transmembrane proteins localized on all synaptic vesicles and is present in three isoforms [30]. SV2 has a crucial role in the regulation of vesicle function, although not in synaptic morphology [31]. In particular, SV2A interacts with the presynaptic protein synaptotagmin, the primary calcium sensor for regulat- ing calcium-dependent exocytosis of synaptic vesicle [32]. It is likely that SV2A indirectly regulates neuro- transmitter release. Thus, modulating SV2A function, levetiracetam could interfere with excitatory transmis- sion, producing a neuroprotective effect [33]. Furthermore, a direct neuroprotective action of leveti- racetam, by regulation of genetic transcription mecha- nisms has been postulated. There is evidence that the major metabolite of levetiracetam blocks histone deacet- ylases in HeLa cells [34]. These enzymes catalyze the hydrolysis of acetyl groups from the lysine of some pro- teins, such as histone tails, inducing chromatin condensa- tion and inhibiting gene transcription [35]. Consequently, histone deacetylase inhibitors, such as levetiracetam modulate the expression of genes crucial for apoptosis. If this experimental finding could be translated into a clin- ical setting, the implications would be promising. 3. Mechanisms of post-stroke epilepsy Stroke is the most common cause of symptomatic epilepsy in older adults [36,37]. Epileptic seizures occur- ring more than 2 weeks after stroke, defined as late- onset post-stroke seizures, are observed in 2–4% of stroke patients [12]. There are different pathophysiolog- ical processes underlying early and late seizures after stroke, with a predominance of acute cellular biochemi- cal disturbances in early seizures and epileptogenic gliot- ic scarring in late seizures [38]. The occurrence of late opment 33 (2011) 289–293 seizures is often delayed for months after the stroke. Development 33 (2011) 289–293 291 Clearly, progressive neuronal changes are underway during this period, which finally result in seizures. Although the critical changes are not clearly under- stood, potential causes of epileptogenesis include selec- tive neuronal cell death and apoptosis, changes in membrane properties, mitochondrial and receptor changes (e.g. loss of GABAergic receptors), deafferenta- tion and collateral sprouting [36]. It has also been pro- posed that the ischemic penumbra of a stroke can contain electrically irritable tissue that provides a focus for seizure activity [39]. The area has been shown to exhibit enhanced release of excitotoxic glutamate, ionic imbalances, breakdown of membrane phospholipids, and release of free fatty acids [40]. Acute ischemia has been shown to increase the extracellular concentrations of glutamate [41,42] and to reduced the GABAergic function, and also the functional or structural impair- ment of GABAergic interneurons. 3.1. Epileptogenesis and levetiracetam Levetiracetam is differentiated from conventional anti- epileptic drugs by its property of not only controlling sei- zures, but also of having an antiepileptogenic effect. In the kindling model of temporal lobe epilepsy levetiracetam administration reduced the development, the severity and the duration of seizures induced by repeated stimula- tion of the amygdala [43]. Furthermore, other experi- ments have shown its long-lasting effect in controlling seizures, prolonged for many days after cessation of the treatment [44]. This effect could be attributed to leveti- racetam’s modification of intrinsic epileptogenic mecha- nisms [44]. Therefore hypothesising that chronic seizures and ischemia behave similarly to cause brain injury [11], levetiracetam could exert its neuroprotective effect by interfering with the underlying epileptogenic mechanisms. 3.2. Levetiracetam in post-stroke seizures Although the prevalence of epilepsy in subjects aged P60 years is higher than in other age groups, level A evidence for the use of AEDs in the elderly, and specif- ically in post-stroke epilepsy, are scanty [12]. So far, the only drug tested in a large population of stroke patients that has been proved to produce long-term freedom from seizures is gabapentin [12]. Among the recently- introduced AEDs, levetiracetam exhibits favourable characteristics: low potential for interaction, no active metabolites, a short elimination half-life [1], no detri- mental effects on sleep architecture, no major negative effects on cognition [45]. These characteristics make it suitable for use in the elderly [46]. Recently, two small prospective observational studies of levetiracetam as monotherapy reported good seizure control in patients V. Belcastro et al. / Brain & with late-onset post-stroke seizures [47,48]. In these studies, approximately 80% of patients became seizure free, with awithdrawal rate due to adverse effects of approximately 15%. Overall, patients were responsive at 1000–2000 mg/day levetiracetam. This find- ingmight reflect the known good response to treatment of epilepsy occurring in elderly people, including post-stroke epilepsy [12,49]. An alternative explanation is that the elderly patients require a lower levetiracetam dose as compared to younger patients because of reduced clear- ance. It has been demonstrated that older adults achieve the same serum levetiracetam levels observed in the young with a mean 40% lower dose [50]. 4. Current and future developments Synaptic and cellular events initiated by acute energy deprivation caused by brain ischemia have been shown to be similar to those triggered by abnormal neuronal dis- charge induced by epilepsy [11]. On the basis of the simi- larity of the cascade of synaptic and intracellular events exhibited by epilepsy and vascular brain injuries, AEDs have been tested as possible neuroprotective agents in ani- mal models of stroke. In common with other new AEDs [11], levetiracetam shows neuroprotective effect in the rat MCA occlusion model with a reduction in infarct vol- ume. However, further studies are needed to investigate the potential role of neuroprotection agents (i.e. AEDs) to improve the prognosis after stroke [36]. The incidence of new-onset epilepsy is higher among the elderly than in any other age group and stroke is the most important cause of symptomatic epilepsy in this frail population [36,37]. New-onset seizures in elderly patients are typically cryptogenic or symptomatic partial seizures that require long-term treatment. Because seizures in the elderly are often readily controlled, considerations of tol- erability and safety, including pharmacokinetics and the potential for drug interactions, may be as important as efficacy in the selection of an antiepileptic drug [12]. The newer AEDs introduced during the past decade offer advantages in this respect over older agents. Among the newer AEDs, levetiracetam exhibits several favourable characteristics as low potential for interaction, no detri- mental effects on sleep architecture and nomajor negative effects on cognition. These observations suggest that lev- etiracetam’s safety and efficacy profile make it an ideal candidate as a first-choice drug for post-stroke seizures. Conflict of interest The authors declare no conflict of interest. References [1] Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet 2004;43:707–24. [2] Arroyo S, Crawford P. Safety profile of levetiracetam. Epileptic Disord 2003;5:S57–63. 292 V. Belcastro et al. / Brain & Development 33 (2011) 289–293 [3] Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJLevetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007;68:402–8. [4] Abou-Khalil B, Schaich L. Long-term efficacy of levetiracetam for partial seizure. Seizure 2005;14:577–85. [5] Grunewald R. Levetiracetam in the treatment of idiopathic generalized epilepsies. Epilepsia 2005;46:154–60. [6] Zesiewicz TA, Sullivan KL, Maldonado JL, Tatum WO, Hauser RA. Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson’s disease. Mov Disord 2005;20:1205–9. [7] Striano P, Manganelli F, Boccella P, Perretti A, Striano S. Levetiracetam in patients with cortical myoclonus: a clinical and electrophysiological study. Mov Disord 2005;20:1610–4. [8] Sullivan KL, Hauser RA, Louis ED, Chari G, Zesiewicz TA. Levetiracetam for the treatment of generalized dystonia. Parkin- sonism Relat Disord 2005;11:468–71. [9] D’Amelio M, Callari G, Gammino M, et al. Levetiracetam in the treatment of vascular corea: a case report. Eur J Clin Pharmacol 2005;60:835–6. [10] PostRM,Altshuler LL, FryeMA, et al. Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder. J Clin Psychiatry 2005;66:370–4. [11] Calabresi P, Cupini ML, Centonze D, Pisani F, Bernardi G. Antiepileptic drugs as a possible neuroprotective strategy of brain ischemia. Ann Neurol 2003;53:693–702. [12] Ryvlin P, Montavont A, Nighoghossian N. Optimizing therapy of seizures in stroke patients. Neurology 2006;67:S3–9. [13] Klitgaard H, Pitkanen A. Antiepiletogenesis, neuroprotection and disease modification in the treatment of epilepsy: focus on levetiracetam. Epileptic Disord 2003;5:S9–S16. [14] Marini H, Costa C, Passaniti M, et al. Levetiracetam protects against kainic acid-induced toxicity. Life Sci 2004;74:1253–64. [15] Hanon E, Klitgaard H. Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusionmodel of focal cerebral ischemia. Seizure 2001;10:287–93. [16] Niespodziany I, Klitgaard H, Margineau DG. Levetiracetam inhibits the high-voltage-activated Ca2+ current in pyramidal neurones of rat hippocampal slices. Neurosci Lett 2001;306:5–8. [17] Angehagen M, Margineau DG, Ben-Menachem E, Ronnback L, Hansson E, Klitgaard H. Levetiracetam reduces caffeine-induced Ca transient and epileptiform potentials in hippocampal neurons. Neuroreport 2003;14:471–5. [18] Pisani A, Bonsi P, Martella G, et al. Intracellular calcium increase in epileptiform activity: modulation by levetiracetam and lamo- trigine. Epilepsia 2004;45:719–28. [19] Lukyanetz EA, Shkryl VM, Kostyuk PG. Selective blockade of N-type calcium channels by levetiracetam. Epilepsia 2002;43:9–18. [20] Zona C, Niespodziany I, Marchetti C, Klitgaard H, Bernardi G, MarginauDG.Levetiracetamdoes notmodulate neuronal voltage- gated Na+ and T-type Ca2+ currents. Seizure 2001;10:279–86. [21] Madeja M, Margineau DG, Gorji A, et al. Reduction of voltage- operated potassium currents by levetiracetam: a novel antiepilep- tic mechanism of action. Neuropharmacology 2003;45:661–71. [22] Green AR, Hainsworth AH, Jackson DM. GABA potentiation: a logical pharmacological approach for the treatment of acute ischemic stroke. Neuropharmacology 2000;39:1438–94. [23] Margineau DG, Klitgaard H. Levtiracetam has not significant c- aminobutyric acid-related effect on pair-pulse interaction in the dentate gyrus of rats. Eur J Pharmacol 2003;466:255–61. [24] Loscher W, Honak D, Bloms-Funke P. 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 1996;735:208–16. [25] Poulain P, Margineau DG. Levetiracetam opposes the action of GABA-A antagonists in hypothalamic neurones. Neuropharma- cology 2002;42:346–52. [26] Bouwman BM, Van Rijn CM. Effects of levetiracetam on spike and wave discharges in WAG/Rij rats. Seizure 2004;13:591–4. [27] Calabresi P, Centonze D, Bernardi G. Cellular factors controlling neuronal vulnerability in the brain: a lesson from the striatum. Neurology 2000;55:1249–55. [28] Noyer M, Gillard M, Matagne A, Henichart JP, Wulfert E. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. Eur J Pharmacol 1995;286:137–46. [29] Stahl SM. Psycopharmacology of anticonvulsants: levetiracetam as a synaptic vesicle protein modulator. J Clin Psychiatry 2004;65:1162–3. [30] Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH. Differential expression of synaptic vesicle protein 2 (SV2) isoform. J Neurosci 1994;14:5223–35. [31] Lamberg N, Gillard M, Vertongen P, Fuks B, Chatelain P. Characterization of 3H-ucb30889 binding to synaptic vesicle protein 2A in the rat spinal cord. Eur J Pharmacol 2005;520:70–6. [32] Bajjalieh SM, Peterson K, Linial M, Scheller RH. Brain contain two forms of synaptic vesicle protein 2. Proc Natl Acad Sci 1993;90:2150–4. [33] Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci 2003;26:9861–6. [34] Eya S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia 2004;45:737–44. [35] De Rujiter A, Van Gennip A, Caron HN, Kemp S, Van Kuilenburg AB. Histone deacetylases: characterization of the classical HADC family. Biochem J 2003;370:737–49. [36] Menon B, Shorvon SD. Ischaemic stroke in adults and epilepsy. Epilepsy Res 2009;87:1–11. [37] Brodie MJ, Elder AT, Kwan P. Epilepsy in later life. Lancet Neurol 2009;8:1019–30. [38] Gupta SR, Naheedy MH, Elias D, Rubino FA. Postinfarction seizures: a clinical study. Stroke 1988;19:1477–81. [39] Heiss WD, Huber M, Fink GR, Herholz K, Pietrzyk U, Wagner R, et al. Progressive derangement of periinfarct viable tissue in ischemic stroke. J Cereb Blood Flow Metab 1992;12:193–203. [40] Reith J, Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS. Seizures in acute stroke: predictors and prognostic significance. The Copenhagen stroke study. Stroke 1997;28:1585–9. [41] Luhmann HJ, Mudrick-Donnon LA, Mittmann T, Heinemann U. Ischemia-induced long-term hyperexcitability in rat neocortex. Eur J Neurosci 1995;7:180–91. [42] Buchkremer-Ratzmann I, August M, Hagemann G, Witte OW. Epileptiform discharges to extracellular stimuli in rat neocortical slices after photothrombotic infarction. J Neurol Sci 1998;156:133–7. [43] Loscher W, Honack D, Runfeldt C. Antiepileptogenic effects of the novel anticonvulsivant levetiracetam (ucbL059) in the kind- ling model of temporal lobe epilepsy. Pharmacol Exp Ther 1998;284:474–9. [44] Ji-qun C, Ishihara K, Nagayama T, Serikawa T, Sasa M. Long- lasting antiepileptic effects of levetiracetam against epileptic seizures in the spontaneously epileptic rat (SER): differentiation of levetiracetam from conventional antiepileptic drugs. Epilepsia 2005;46:1362–70. [45] Meador KJ, Gevins A, Loring DW, et al. Neuropsychological and neurophysiologic effects of carbamazepine and levetiracetam. Neurology 2007;69:2076–84. [46] Belcastro V, Costa C, Galletti F, et al. Levetiracetam mono- therapy in Alzheimer patients with late-onset seizures: a prospec- tive observational study. Eur J Neurol 2007;14:1176–8. [47] Belcastro V, Costa C, Galletti F, et al. Levetiracetam in newly diagnosed late-onset post-stroke seizures: a prospective observa- tional study. Epilepsy Res 2008;82:223–6. [48] Kutlu G, Gomceli YB, Unal Y, Inan LE. Levetiracetam mono- therapy for late poststroke seizures in the elderly. Epilepsy Behav 2008;13:542–4. [49] Leppik IE. Epilepsy in the elderly. Epilepsia 2006;47:65–70. [50] Hirsch LJ, Arif H, Buchsbaum R, et al. Effect of age and comedication on levetiracetam pharmacokinetics and tolerability. Epilepsia 2007;48:1351–9. V. Belcastro et al. / Brain & Development 33 (2011) 289–293 293 Levetiracetam in brain ischemia: clinical Clinical implications in neuroprotection and prevention of post-stroke epilepsy Introduction Neuroprotection in brain ischemia: potential mechanisms of levetiracetam Mechanisms of post-stroke epilepsy Epileptogenesis and levetiracetam Levetiracetam in post-stroke seizures Current and future developments Conflict of interest References