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Brain & Development 33 (2011) 289–293

Mini review

Levetiracetam in brain ischemia: Clinical implicationsin neuroprotection and prevention of post-stroke epilepsy

Vincenzo Belcastro a,*, Laura Pierguidi a, Nicola Tambasco b

a Neurology Clinic, S. Anna Hospital, Como, Italyb Neurology Clinic, University of Perugia, Italy

Received 5 February 2010; received in revised form 2 June 2010; accepted 4 June 2010

Abstract

Several new antiepileptic drugs (AEDs) have been introduced for clinical use recently. These new AEDs, like the classic AEDs,target multiple cellular sites both pre- and postsynaptically. The use of AEDs as a possible neuroprotective strategy in brain ische-mia is receiving increasing attention and the antiepileptic drug levetiracetam, a 2S-(2-oxo-1-pyrrolidiny1) butanamide, belonging tothe pyrrolidone family, could have a crucial role in regulation of epileptogenesis and neuroprotection. Recent observations suggestthat levetiracetam is both safe and effective against post-stroke seizures. In this review, the potential neuroprotective role in brainischemia 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 drugswith a wide spectrum of actions, such as antiepileptic andneuroprotective functions [1,2]. Levetiracetam isapproved as monotherapy in partial epilepsy with orwithout secondary generalization [3], and it maintainsits efficacy and safety during long-term therapy [4]. More-over, levetiracetam may be employed alone or in combi-nations with valproate, lamotrigine or phenobarbital inthe treatment of idiopathic generalized epilepsies [5].

Furthermore, levetiracetam shows a particularlygood balance between efficacy and tolerability, not onlyin the management of epilepsy but also in movement [6–9] and mood disorders [10]. Interestingly, levetiracetam

0387-7604/$ - see front matter � 2010 The Japanese Society of Child Neuro

doi:10.1016/j.braindev.2010.06.008

* Corresponding author. Address: Clinica Neurologica, AziendaOspedaliera Sant’Anna, via Napoleona, 60-22100 Como, Italy. Tel.:+39 3485452889.

E-mail address: vincenzobelcastro@libero.it (V. Belcastro).

might have a neuroprotective role against ischemic braininjury [11].

In the elderly, the incidence of new-onset epilepsy ishigher than in any other age group and, in this frail pop-ulation, the most cause of symptomatic epilepsy is repre-sented by stroke [12]. Usually, elderly patients becomeseizure free with relatively low doses of antiepilepticdrugs (AEDs); nevertheless, comorbidities and comedi-cations frequently raise concerns about potentially detri-mental drug interactions [12]. Among the recently-introduced AEDs, levetiracetam exhibits favourablecharacteristics which make it an ideal candidate as afirst-choice drug for post-stroke seizures.

This review discusses the potential neuroprotectiverole in brain ischemia and the therapeutic implicationsof levetiracetam in post-stroke epilepsy.

2. Neuroprotection in brain ischemia: potential

mechanisms of levetiracetam

On the basis of the similarity of the cascade of synap-tic and intracellular events exhibited by epilepsy and

logy. Published by Elsevier B.V. All rights reserved.

290 V. Belcastro et al. / Brain & Development 33 (2011) 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 mayhave a crucial role in the regulation of epileptogenesisand neuroprotection [13]. Some particular mechanismsof action of levetiracetam might be involved in neuro-protection after vascular injury (Table 1).

Experimental observations have demonstrated thatlevetiracetam has a direct ability to protect against theneurotoxicity induced by chemical compounds such askainic acid [14].

Interestingly, levetiracetam’s neuroprotective proper-ties have been investigated in the rat middle cerebralartery (MCA) occlusion model, a condition of focal cere-bral ischemia [15]. In this study, application of levetirace-tam reduced the infarct volume without altered bodytemperature, with better results than those obtained byapplication of a non-competitive N-methyl-D-asparticacid (NMDA) antagonist [15].

The influx of calcium into cells triggers the cascade ofevents that brings about cell death, so it is possible thatselective 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 incontrolling the release of neurotransmitters, while Lchannels regulate signalling events at a postsynapticlevel. It is likely that the selective modulation of Nand P/Q subtypes could be effective as a neuroprotectivestrategy [11]. In this sense, levetiracetam could be con-sidered, because it regulates the influx of calcium intothe cells [16–18], selectively blocking N-type [19], butnot the T-type channel [20]. Moreover, there is evidencethat levetiracetam reduces the flow of potassium withinthe 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 1Summary of the potential mechanisms of levetiracetam relevant toneuroprotection.

Species Model Mechanism Reference

Rat Kainic acid Inhibition oflipid peroxidation

[14]

Rat Hippocampalneurons in culture

Inhibition ofCa release

[16,17]

Rat HippocampalCA1 neurons

Reduction ofpotassium currents

[21]

Rat Striatal neurons Alterations inGABA metabolismand 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 cancercells taken from a patient named Henrietta Lacks.

strongly depressed during brain ischemia [11]. Thereforeall pre- and postsynaptic strategies supporting andincreasing GABAergic levels could exerts a neuroprotec-tive effect [22]. Although levetiracetam does not directlymodulate the GABAergic system [23], it could interferewith GABA turnover [24] and with the action of GABA-A antagonists [25], as possible further mechanisms ofthe neuroprotective effect [26].

Negative regulation of excitatory transmission can beconsidered a prominent protection strategy againstischemia [27]. Modulation of ionotropic and metabotro-pic (group I) glutamatergic receptors has to be consid-ered the main mechanism of neuroprotection. There isno evidence of a direct interaction between levetiracetamwith glutamate receptors, but a role could be postulatedin negative modulation of excitatory transmission,through a specific link to a site in the central nervoussystem membranes [28]. In particular, it has been dem-onstrated that levetiracetam binds to a synaptic vesicleprotein called SV2A [29]. This is the most expressed typeof a family of integral transmembrane proteins localizedon all synaptic vesicles and is present in three isoforms[30]. SV2 has a crucial role in the regulation of vesiclefunction, although not in synaptic morphology [31]. Inparticular, SV2A interacts with the presynaptic proteinsynaptotagmin, 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 themajor metabolite of levetiracetam blocks histone deacet-ylases in HeLa cells [34]. These enzymes catalyze thehydrolysis 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 levetiracetammodulate 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 symptomaticepilepsy 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% ofstroke patients [12]. There are different pathophysiolog-ical processes underlying early and late seizures afterstroke, with a predominance of acute cellular biochemi-cal disturbances in early seizures and epileptogenic gliot-ic scarring in late seizures [38]. The occurrence of lateseizures is often delayed for months after the stroke.

V. Belcastro et al. / Brain & Development 33 (2011) 289–293 291

Clearly, progressive neuronal changes are underwayduring 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 inmembrane properties, mitochondrial and receptorchanges (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 cancontain electrically irritable tissue that provides a focusfor seizure activity [39]. The area has been shown toexhibit enhanced release of excitotoxic glutamate, ionicimbalances, breakdown of membrane phospholipids,and release of free fatty acids [40]. Acute ischemia hasbeen shown to increase the extracellular concentrationsof glutamate [41,42] and to reduced the GABAergicfunction, 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 thekindling model of temporal lobe epilepsy levetiracetamadministration reduced the development, the severityand the duration of seizures induced by repeated stimula-tion of the amygdala [43]. Furthermore, other experi-ments have shown its long-lasting effect in controllingseizures, prolonged for many days after cessation of thetreatment [44]. This effect could be attributed to leveti-racetam’s modification of intrinsic epileptogenic mecha-nisms [44]. Therefore hypothesising that chronicseizures and ischemia behave similarly to cause braininjury [11], levetiracetam could exert its neuroprotectiveeffect by interfering with the underlying epileptogenicmechanisms.

3.2. Levetiracetam in post-stroke seizures

Although the prevalence of epilepsy in subjects agedP60 years is higher than in other age groups, level Aevidence for the use of AEDs in the elderly, and specif-ically in post-stroke epilepsy, are scanty [12]. So far, theonly drug tested in a large population of stroke patientsthat has been proved to produce long-term freedomfrom seizures is gabapentin [12]. Among the recently-introduced AEDs, levetiracetam exhibits favourablecharacteristics: low potential for interaction, no activemetabolites, a short elimination half-life [1], no detri-mental effects on sleep architecture, no major negativeeffects on cognition [45]. These characteristics make itsuitable for use in the elderly [46]. Recently, two smallprospective observational studies of levetiracetam asmonotherapy reported good seizure control in patientswith late-onset post-stroke seizures [47,48].

In these studies, approximately 80% of patientsbecame seizure free, with a withdrawal rate due to adverseeffects of approximately 15%. Overall, patients wereresponsive at 1000–2000 mg/day levetiracetam. This find-ing might reflect the known good response to treatment ofepilepsy occurring in elderly people, including post-strokeepilepsy [12,49]. An alternative explanation is that theelderly patients require a lower levetiracetam dose ascompared to younger patients because of reduced clear-ance. It has been demonstrated that older adults achievethe same serum levetiracetam levels observed in the youngwith a mean 40% lower dose [50].

4. Current and future developments

Synaptic and cellular events initiated by acute energydeprivation caused by brain ischemia have been shownto 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 eventsexhibited by epilepsy and vascular brain injuries, AEDshave been tested as possible neuroprotective agents in ani-mal models of stroke. In common with other new AEDs[11], levetiracetam shows neuroprotective effect in therat MCA occlusion model with a reduction in infarct vol-ume. However, further studies are needed to investigatethe potential role of neuroprotection agents (i.e. AEDs)to improve the prognosis after stroke [36].

The incidence of new-onset epilepsy is higher amongthe elderly than in any other age group and stroke is themost important cause of symptomatic epilepsy in this frailpopulation [36,37]. New-onset seizures in elderly patientsare typically cryptogenic or symptomatic partial seizuresthat require long-term treatment. Because seizures in theelderly are often readily controlled, considerations of tol-erability and safety, including pharmacokinetics and thepotential for drug interactions, may be as important asefficacy in the selection of an antiepileptic drug [12]. Thenewer AEDs introduced during the past decade offeradvantages in this respect over older agents. Among thenewer AEDs, levetiracetam exhibits several favourablecharacteristics as low potential for interaction, no detri-mental effects on sleep architecture and no major negativeeffects on cognition. These observations suggest that lev-etiracetam’s safety and efficacy profile make it an idealcandidate as a first-choice drug for post-stroke seizures.

Conflict of interest

The authors declare no conflict of interest.

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