Levetiracetam does not modulate neuronal voltage-gated Na+and T-type Ca2+currents

Zona, Cristina; Niespodziany, Isabelle; Marchetti, Caterina; Klitgaard, Henrik; Bernardi, Giorgio; Margineanu, Doru Georg

doi:10.1053/seiz.2000.0504

Cited by 136 publications

(96 citation statements)

References 23 publications

(31 reference statements)

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“…This appears to exclude that a direct facilitation by LEV of GABAergic inhibition is involved in its anti-epileptic activity in humans. Together with reports showing an absence of eect on both voltage-operated Na + and T-type Ca 2+ currents (Zona et al, 2001), this suggests that LEV does not induce a conventional modulation of any of the three main mechanisms involved in the anti-epileptic action of classical AEDs. Instead, the present study revealed that LEV was the only AED showing a consistent suppression of the inhibition by both bcarbolines and zinc on GABA-and glycine-gated currents.…”

Section: Discussionsupporting

confidence: 70%

“…Recent studies have shown that LEV is devoid of impact on the voltage-activated tetrodotoxin-sensitive inward Na + current in cultured rat cortical neurons and on the low-voltage-activated (T-type) Ca 2+ current in pyramidal neurons from rat hippocampal slices (Zona et al, 2001). This suggests that inhibition of voltage-operated Na + or T-type Ca 2+ channels is not involved in the anti-epileptic mechanism of LEV.…”

Section: Introductionmentioning

confidence: 99%

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The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

Rigo

Hans

Nguyen

et al. 2002

British J Pharmacology

307

178

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1 In this study in vitro and in vivo approaches were combined in order to investigate if the antiepileptic mechanism(s) of action of levetiracetam (LEV; Keppra 1 ) may involve modulation of inhibitory neurotransmission. 2 GABA-and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The eect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam, phenobarbital and ethosuximide. 3 LEV contrasted the reference AEDs by an absence of any direct eect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4 These minor direct eects contrasted with a potent ability of LEV (EC 50 =1 ± 10 mM) to reverse the inhibitory eects of the negative allosteric modulators zinc and b-carbolines on both GABA A and glycine receptor-mediated responses. . In contrast, the benzodiazepine receptor antagonist¯umazenil (up to 10 mg kg 71) was without any eect on the protection aorded by LEV. 7 The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the antiepileptic mechanism(s) of action of LEV.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

Rigo

Hans

Nguyen

et al. 2002

British J Pharmacology

307

178

View full text Add to dashboard Cite

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“…7 LEV seems to partially inhibit N-type high voltage-activated Ca 2+ currents and reduces Ca 2+ release from intraneuronal stores; it reverses the effects of negative allosteric modulators of gamma aminobutyric acid and glycine-gated currents. [8][9][10] Recently, the LEV binding site was identified as synaptic vesicle protein 2A (SV2A). 11 A very recent study 12 has explored the hypothesis that the antiepileptic mechanism of action of LEV is related to effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels in mouse cortical neurons.…”

mentioning

confidence: 99%

Levetiracetam in juvenile myoclonic epilepsy: long‐term efficacy in newly diagnosed adolescents

Verrotti

Cerminara

Coppola

et al. 2007

Develop Med Child Neuro

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The aim of this study was to evaluate the efficacy and tolerability of levetiracetam (LEV) monotherapy in juvenile myoclonic epilepsy (JME). The study group consisted of 32 patients with epilepsy (20 males, 12 females) with a mean age of 13 years 3 months (SD 7y 11mo) at seizure onset. LEV was administered as the first drug; all patients were followed up at 6 and 12 months. The dose that achieved seizure control ranged from 1000 to 2500mg/daily. At 6-month evaluation: 15 patients were seizure free; 14 patients were responders (>50% reduction in seizures); and three patients had marginal effects (<50% reduction of seizures). At 12-month evaluation: 29 patients were seizure free; three patients were responders. No patients reported adverse events. These data provide preliminary evidence that LEV may be effective for treating patients with newly diagnosed JME.Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy, characterized by irregular myoclonic jerks, tonicclonic seizures, and sometimes typical absences. 1 The main clinical symptoms of JME are myoclonic jerks on awakening, generalized tonic-clonic seizures, typical absences, and photosensitivity. 1,2 This type of epilepsy generally responds to antiepileptic drugs (AEDs) and is, therefore, generally considered a benign type of epilepsy. 3 Physicians have at their disposal many AEDs to treat JME; historically, valproic acid was the first AED used to treat myoclonic seizures, 4 but levetiracetam (LEV) could be a good alternative because of its efficacy against all three JME seizure types and photosensitivity, and because of lack of the endocrine and metabolic side-effects frequently reported in patients receiving valproic acid. 5,6 LEV is a novel AED because its mechanisms of action appear different from other AEDs and seem to be unrelated to known mechanisms of neurotransmission. In fact, it has no significant affinity for gamma-aminobutyric acidergic or glutamatergic receptors and does not interact directly with the benzodiazepine binding site. 7 LEV seems to partially inhibit N-type high voltage-activated Ca 2+ currents and reduces Ca 2+ release from intraneuronal stores; it reverses the effects of negative allosteric modulators of gamma aminobutyric acid and glycine-gated currents. [8][9][10] Recently, the LEV binding site was identified as synaptic vesicle protein 2A (SV2A). 11 A very recent study 12 has explored the hypothesis that the antiepileptic mechanism of action of LEV is related to effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels in mouse cortical neurons. This study reveals that AMPA receptors are modulated by LEV because a significant decrease was found in the kainate and AMPA-induced miniature excitatory postsynaptic currents in cortical neurons.Several reports and open label studies have pointed out the efficacy of LEV in generalized epilepsy. [13][14][15][16] Moreover, LEV has been shown to be effective in preventing the photoparoxysmal response in patients with photosensitive epile...

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“…Action mechanism of levetiracetam has not been understood clearly yet (37). It is thought in some studies related to the action mechanism of levetiracetam that it regulates highvoltage N-type calcium channels and potassium flow (22).…”

Section: Resultsmentioning

confidence: 99%

The effects of levetiracetam on neural tube development in the early stage of chick embryos

Güvenç¹,

Dalgıç²,

Billur³

et al. 2013

Turkish Neurosurgery

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AIm: This study aimed to investigate the effects of a new generation antiepileptic agent, levetiracetam, on the neural tube development in a chick embryo model that corresponds to the first month of vertebral development in mammals. mAteRIAl and methods: Forty-five Atabey® breed fertilized chicken eggs with no specific pathogens were randomly divided into 5 groups. All of the eggs were incubated at 37.8±2°C and 60±5 % relative humidity in an incubator. Group A was control group. The other eggs were applied physiological saline and drugs at a volume of 10 µL by the in ovo method at the 28th hour of the incubation period. Group B was given distilled water; Group C, physiological saline; Group D, Levetiracetam (L8668) at a dose equivalent to the treatment dose for humans (10 mg/ kg), and Group E, Levetiracetam (L8668) at a dose of 10 times the treatment dose. The embryos in all of the groups were removed from the shells at the 48th hour and morphologically and histologically evaluated. Results:Of the 45 embryos incubated, neural tubes of 41 were closed and the embryos displayed normal development. ConClusIon:Levetiracetam, at a dose equivalent to human treatment dose and 10 times the treatment dose, was shown not to cause neural tube defects in chick embryos. KeywoRds: Levetiracetam, Chick embryo, Neural tube defect ÖZAmAÇ: Bu çalışmada yeni bir antiepileptik ajan olan levetirasetamın memelilerde embriyonel omurga gelişiminin ilk ayına uyan erken dönem civciv embriyo modelinde nöral tüp gelişimi üzerine olan etkilerinin incelenmesi amaçlanmıştır. yÖntem ve GeReÇleR: Çalışma için spesifik patojen içermeyen 45 adet Atabey® cinsi döllenmiş tavuk yumurtası rastgele 5 gruba ayrıldı. Tüm yumurtalar 37.8±2°C sıcaklık ve % 60±5 nem oranında kuluçka makinasında inkübe edildi. Grup A kontrol grubu olarak ayrıldı. Diğer yumurtalara ise inkübasyonun 28. saatinde 10 µL hacim içerisinde in-ovo yöntem ile serum fizyolojik ve ilaç uygulamaları yapıldı. Grup B'ye distile su, Grup C'ye serum fizyolojik, Grup D'ye insanda kullanılan tedavi dozuna (10 mg/kg) eşdeğer dozda levatirasetam ( L8668 ) ve Grup E'ye bu tedavi dozunun 10 katı yükseklikte levetirasetam verildi. Tüm gruplardaki embriyolar 48. saatte yumurtadan çıkarılarak morfolojik ve histolojik olarak incelendi.BulGulAR: İnkübe edilen 45 adet embriyonun 41'inde nöral tüpün kapalı olduğu ve embriyonun normal gelişim gösterdiği görüldü. sonuÇ: Levetirasetam'ın insan tedavi dozuna eşdeğer dozda ve bu değerin 10 katı yükseklikte verilen dozlarda civciv embriyosunda nöral tüp defekti oluşturmadığı gözlemlenmiştir.

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Levetiracetam does not modulate neuronal voltage-gated Na+and T-type Ca2+currents

Cited by 136 publications

References 23 publications

The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

Levetiracetam in juvenile myoclonic epilepsy: long‐term efficacy in newly diagnosed adolescents

The effects of levetiracetam on neural tube development in the early stage of chick embryos

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