Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?

Madeja, Michael; Margineanu, Doru Georg; Gorji, Ali; Siep, E.; Boerrigter, Paulus Maria; Klitgaard, Henrik; Speckmann, Erwin‐Josef

doi:10.1016/s0028-3908(03)00248-x

Cited by 135 publications

(89 citation statements)

References 34 publications

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“…Although LEV did not affect Na ϩ -and low-voltageactivated Ca V channels (Zona et al, 2001), it was reported to inhibit high-voltage-activated Ca V channels; those effects occurred in response to short-term LEV application (Lukyanetz et al, 2002;Pisani et al, 2004;Costa et al, 2006;Martella et al, 2008), although one study reported that LEV action on Ca V channels required prolonged exposure . LEV inhibition of delayed rectifier K ϩ channels also was reported (Madeja et al, 2003). Moreover, brivaracetam and seletracetam inhibit Na ϩ channels and high-voltage-activated Ca V channels, respectively (Martella et al, 2009;Zona et al, 2010), which suggests distinct, direct, ion channel blockade by different SV2A ligands, although it remains unclear whether effects on ion channels are independent of SV2A-mediated interactions.…”

Section: Introductionmentioning

confidence: 74%

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca²⁺ Channels through an Intracellular Pathway

Vogl¹,

Mochida²,

Wolff³

et al. 2012

Mol Pharmacol

109

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Levetiracetam (LEV) is a prominent antiepileptic drug that binds to neuronal synaptic vesicle glycoprotein 2A protein and has reported effects on ion channels, but with a poorly defined mechanism of action. We investigated inhibition of voltagedependent Ca 2ϩ (Ca V ) channels as a potential mechanism through which LEV exerts effects on neuronal activity. We used electrophysiological methods to investigate the effects of LEV on cholinergic synaptic transmission and Ca V channel activity in superior cervical ganglion neurons (SCGNs). In parallel, we investigated the effects of the inactive LEV R-enantiomer, (R)-␣-ethyl-2-oxo-1-pyrrolidine acetamide (UCB L060). LEV but not UCB L060 (each at 100 M) inhibited synaptic transmission between SCGNs in long-term culture in a time-dependent manner, significantly reducing excitatory postsynaptic potentials after a Ն30-min application. In isolated SCGNs, LEV pretreatment (Ն1 h) but not short-term application (5 min) significantly inhibited whole-cell Ba 2ϩ current (I Ba ) amplitude. In currentclamp recordings, LEV reduced the amplitude of the afterhyperpolarizing potential in a Ca 2ϩ -dependent manner but also increased the action potential latency in a Ca 2ϩ -independent manner, which suggests additional mechanisms associated with reduced excitability. Intracellular LEV application (4 -5 min) caused rapid inhibition of I Ba amplitude, to an extent comparable to that seen with extracellular LEV pretreatment (Ն1 h). Neither pretreatment nor intracellular application of UCB L060 produced any inhibitory effects on I Ba amplitude. These results identify a stereospecific intracellular pathway through which LEV inhibits presynaptic Ca V channels; resultant reductions in neuronal excitability are proposed to contribute to the anticonvulsant effects of LEV.

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Section: Introductionmentioning

confidence: 74%

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca²⁺ Channels through an Intracellular Pathway

Vogl¹,

Mochida²,

Wolff³

et al. 2012

Mol Pharmacol

109

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“…155 Lamotrigine, however, was found to reduce the amplitude of A-type K ϩ currents in cultured hippocampal neurons 156 and levetiracetam was reported to inhibit delayed rectifier but not A-type K ϩ currents in isolated hippocampal neurons. 157 These inhibitory actions would be expected to enhance excitability and are unlikely to contribute to anticonvulsant activity. Lamotrigine also blocks hERG, the human ether-à-go-go K ϩ channel (KCNHZ), that would be proarrhythmic in the heart 158 and might favor sudden unexpected death in epilepsy (SUDEP), which is a significant problem in adults with poorly controlled seizures.…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…[11] Levetiracetam also regulates the influx of calcium into the cells, and modulates membrane depolarization and prevents irreversible cellular damage. [31][32][33] In this present study we determined the protective antioxidant effects of LEV on hepatic fibrosis. Significant increases were detected in the serum levels of GSH and TAC while there was a significant decrease in the serum levels of MDA in the LEV+STZ group.…”

Section: Discussionmentioning

confidence: 97%

Effect of levetiracetam on hepatic fibrosis in diabetic rats

Uyanıkgil

Akman

Çavuşoğlu³

et al. 2015

FNG & Bilim Tıp Dergisi

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Objectives: In our study we investigated the possible effects of levetiracetam (LEV) on hepatic fibrosis in streptozotocin (STZ) induced diabetic rats with histopathology, real-time elastography imaging technique. We also aimed to investigate the effects of LEV on oxidative stress markers. Materials and methods: Diabetes was induced by intraperitoneal (i.p.) single dose injection of STZ (60 mg/kg). Twenty-one rats were randomly divided into three groups; control group, STZ group treated with 1 mL/kg/day saline (STZ+SP), and STZ group treated with 600 mg/kg/day LEV was administrated by i.p. for four weeks. All rats underwent a real-time elastography (strain-elasticity %). The liver sections are examined by histopathologically (liver fibrosis score). In addition, malondialdehyde, total antioxidant capacity, and glutathione levels were measured in plasma. Results: Treatment with LEV significantly decreased liver fibrosis score and increased strain measurement % on the real-time elastography in diabetic rats. In addition, treatment with LEV significantly increased total antioxidant capacity, glutathione and malondialdehyde levels decreased in plasma of diabetic rats. Conclusion: Levetiracetam has potential as a treatment for diabetic liver injury and hepatic fibrosis and can be a good candidate among new treatment options. In addition, real-time elastography is reliable imaging non-invasive technique for detecting hepatic fibrosis.Keywords: Diabetes mellitus; levetiracetam; oxidative stress; real-time elastography.Diyabetik sıçanlarda karaciğer fibrozisi üzerine levetirasetam etkisi ÖZ Amaç: Bu çalışmada, streptozotocin (STZ) ile indüklenmiş diyabetik sıçanlardaki hepatik fibrozis üzerine levetirasetamın (LEV) pozitif etkilerinin histopatolojik ve gerçek zamanlı elastografik görüntüleme tekniği ile incelenmesi amaçlandı. Yine bu çalışmada LEV'nin oksidatif stres belirteçleri üzerine etkisi araştırıldı. Gereç ve yöntemler: Diyabetik model, tek doz intraperitoneal (i.p.) STZ (60 mg/kg) enjeksiyonu ile yapıldı. Yirmi bir sıçan rastgele olarak üç gruba ayrıldı; kontrol grubu, STZ uygulaması yapılıp 1 mL/kg/gün salin verilen grup (STZ+SP) ve STZ uygulanıp dört hafta boyunca 600 mg/kg/gün i.p LEV uygulanan grup. Tüm sıçanlar gerçek zamanlı elastografik yöntem ile incelendi (gerilme-elastikiyet yüzdesi). Karaciğerden alınan kesitler histopatolojik olarak değerlendirildi (karaciğer fibroz skoru). Bunlara ek olarak, plazmadan malondialdehit, total antioksidant kapasite ve glutatyon seviyeleri ölçüldü. Bulgular: Levetirasetam ile tedavi edilen diyabetik sıçanlarda karaciğer fibroz skorlamasında anlamlı bir azalma ve gerçek zamanlı elastografik gerilim-elastikiyet yüzdesinde artış saptandı. Bununla birlikte LEV tedavisinde diyabetik sıçanlarda total antioksidant kapasitesinin arttığı, glutatyon ve malondialdehitin plazma seviyelerinin azaldığı görüldü. Sonuç: Levetirasetam, diyabetik karaciğer hasarı ve karaciğer fibrozisi için yeni tedavi seçenekleri arasında iyi bir aday olabilir. Buna ek olarak gerçek zamanlı elasto...

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Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?

Cited by 135 publications

References 34 publications

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca²⁺ Channels through an Intracellular Pathway

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca²⁺ Channels through an Intracellular Pathway

Molecular Targets for Antiepileptic Drug Development

Effect of levetiracetam on hepatic fibrosis in diabetic rats

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Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?

Cited by 135 publications

References 34 publications

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca2+ Channels through an Intracellular Pathway

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca2+ Channels through an Intracellular Pathway

Molecular Targets for Antiepileptic Drug Development

Effect of levetiracetam on hepatic fibrosis in diabetic rats

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The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca²⁺ Channels through an Intracellular Pathway

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca²⁺ Channels through an Intracellular Pathway