Brivaracetam (ucb 34714) inhibits Na+ current in rat cortical neurons in culture

Zona, Cristina; Pieri, Massimo; Carunchio, Irene; Curcio, Livia; Klitgaard, Henrik; Margineanu, Doru Georg

doi:10.1016/j.eplepsyres.2009.09.024

Cited by 67 publications

(69 citation statements)

References 32 publications

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“…The high-affinity SV2A ligand brivaracetam does not bind or modulate Ca V channels (Gillard et al, 2011) but is a Na ϩ channel blocker, at least during short-term application (Zona et al, 2010). Such different effects suggest that SV2A binding per se may not dictate a common inhibitory mechanism; differences in molecular structures between SV2A ligands (and enantiomeric forms, at least for LEV) might confer differential ion channel inhibition as their ultimate mechanism of action.…”

Section: B Amentioning

confidence: 99%

“…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: 99%

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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: B Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Like levetiracetam, brivaracetam binds to the synaptic vesicle protein 2A, but with higher affinity; brivaracetam also inhibits sodium channels [Gazzola et al 2011;Zona et al 2010]. An exploratory, phase IIb, double-blind, randomized, parallel-group, placebo-controlled study using brivaracetam doses of 5, 20, or 50 mg/day was performed; tolerability was good, with only 2.6% of patients discontinuing drug due to AEs, compared with 3.7% of patients in the placebo arm [French et al 2010].…”

Section: General Concepts: Old Versus New Aedsmentioning

confidence: 99%

New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

French

Gazzola

2011

Therapeutic Advances in Drug Safety

114

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Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been introduced to the US market. Randomized, placebo-controlled trials have yielded information about each drug's efficacy, tolerability, and safety profile; however, few studies have compared the newer generation AEDs directly with the older generation. Comparative studies are not always straightforward in their interpretation, as many characteristics of drugs, both favorable and unfavorable, may not be highlighted by such studies. In general, findings from the literature suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufinamide, and lacosamide) enjoy both improved tolerability and safety compared with older agents such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by some of the findings of the QSS and the TTA Committee of the American Academy of Neurology (AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is discussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topiramate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs. The findings of the SANAD trial are also presented; when administered to patients with partial epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to AEs. When administered to patients with idiopathic generalized epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed by valproate; and while valproate was the most efficacious drug in this arm of the study, lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique is its head-to-head comparison of one drug with another. Such comparative trials are overall lacking for new AEDs, although some conclusions can be drawn from the available data. In the end, however, AED selection must be based on individual patient and drug characteristics.

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“…As with most AEDs, brivaracetam likely has multiple mechanisms of action. Not only is it an SV2A ligand, it displays inhibitory activity at neuronal voltage-dependent sodium channels (8).…”

Section: Brivaracetam a Novel Antiepileptic Drug: Is It Effective Anmentioning

confidence: 99%

Brivaracetam, a Novel Antiepileptic Drug: Is it Effective and Safe? Results from One Phase III Randomized Trial

Pack¹

2014

Epilepsy Curr

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In Clinical ScienceCommentary Despite the availability of multiple AEDs, many patients with epilepsy continue to have refractory seizures as well as debilitating side effects. As such, there continues to be a need to explore and investigate new AEDs. Brivaracetam is a novel compound that has been studied extensively in preclinical, phase II, and now phase III trials. The results of three phase III, prospective multicenter randomized, double-blind placebocontrolled, parallel-group trials have recently been published (1-3) and yield mixed results.Brivaracetam is a high-affinity synaptic vesicle protein 2A (SV2A) ligand. It is not entirely clear how SV2A affects neurotransmission, but animal studies suggest that it is potentially a good target for seizure control. Mice deficient in SV2A have seizures (4). Among animal models of epileptogenesis as well

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Brivaracetam (ucb 34714) inhibits Na+ current in rat cortical neurons in culture

Cited by 67 publications

References 32 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

New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

Brivaracetam, a Novel Antiepileptic Drug: Is it Effective and Safe? Results from One Phase III Randomized Trial

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Brivaracetam (ucb 34714) inhibits Na+ current in rat cortical neurons in culture

Cited by 67 publications

References 32 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

New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

Brivaracetam, a Novel Antiepileptic Drug: Is it Effective and Safe? Results from One Phase III Randomized Trial

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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