Brivaracetam Differentially Affects Voltage‐Gated Sodium Currents Without Impairing Sustained Repetitive Firing in Neurons

Niespodziany, Isabelle; André, Véronique; Leclère, Nathalie; Hanon, Étienne; Ghisdal, Philippe; Wolff, Christian

doi:10.1111/cns.12347

Cited by 42 publications

(36 citation statements)

References 35 publications

(69 reference statements)

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“…Indeed, a well‐known feature of AEDs with a primary mechanism of action on voltage‐gated sodium channels is an efficient inhibition of sustained repetitive firing. However, additional studies with BRV in this experimental paradigm, even at supratherapeutic concentrations, showed BRV to be ineffective in reducing the neuronal firing (Table ) . This later study confirmed that minor inhibition of the transient currents of voltage‐gated sodium channels by BRV does not appear to translate into physiologically relevant effects on the intrinsic firing properties of neurons .…”

Section: Mechanism Of Actionsupporting

confidence: 53%

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

et al. 2016

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SUMMARYDespite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures. The discovery of BRV was triggered by the novel mechanism of action and atypical properties of levetiracetam (LEV) in preclinical seizure and epilepsy models. LEV is associated with several mechanisms that may contribute to its antiepileptic properties and adverse effect profile. Early findings observed a moderate affinity for a unique brain-specific LEV binding site (LBS) that correlated with anticonvulsant effects in animal models of epilepsy. This provided a promising molecular target and rationale for identifying selective, high-affinity ligands for LBS with potential for improved antiepileptic properties. The later discovery that synaptic vesicle protein 2A (SV2A) was the molecular correlate of LBS confirmed the novelty of the target. A drug discovery program resulted in the identification of anticonvulsants, comprising two distinct families of high-affinity SV2A ligands possessing different pharmacologic properties. Among these, BRV differed significantly from LEV by its selective, high affinity and differential interaction with SV2A as well as a higher lipophilicity, correlating with more potent and complete seizure suppression, as well as a more rapid brain penetration in preclinical models. Initial studies in animal models also revealed BRV had a greater antiepileptogenic potential than LEV. These properties of BRV highlight its promising potential as an AED that might provide broad-spectrum efficacy, associated with a promising tolerability profile and a fast onset of action. BRV represents the first selective SV2A ligand for epilepsy treatment and may add a significant contribution to the existing armamentarium of AEDs.

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Section: Mechanism Of Actionsupporting

confidence: 53%

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

et al. 2016

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“…Compound A showed potent activity on recombinant Kv1.1/Kvβ1 channels which prompted us to further validate the effects of the ligand on sustained repetitive firing in hippocampal slices from adult rats. The increase of the intrinsic excitability of neurons, leading to sustained bursting activity, is a major cellular feature of epileptiform activity and antiepileptic drugs acting on voltage‐gated sodium channels were shown to reduce sustained repetitive firing in neurons . We verified that compound A does not modulate TTX‐sensitive voltage‐gated sodium currents (in N1E‐115 neuroblastoma cells; data not shown) further indicating that the molecular mechanism of compound A differentiates from classical antiepileptic drugs.…”

Section: Discussionmentioning

confidence: 67%

Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity

et al. 2018

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Summary Aims Kv1.1 (KCNA1) channels contribute to the control of neuronal excitability and have been associated with epilepsy. Kv1.1 channels can associate with the cytoplasmic Kvβ1 subunit resulting in rapid inactivating A‐type currents. We hypothesized that removal of channel inactivation, by modulating Kv1.1/Kvβ1 interaction with a small molecule, would lead to decreased neuronal excitability and anticonvulsant activity. Methods We applied high‐throughput screening to identify ligands able to modulate the Kv1.1‐T1 domain/Kvβ1 protein complex. We then selected a compound that was characterized on recombinant Kv1.1/Kvβ1 channels by electrophysiology and further evaluated on sustained neuronal firing and on in vitro epileptiform activity using a high K+‐low Ca2+ model in hippocampal slices. Results We identified a novel compound able to modulate the interaction of the Kv1.1/Kvβ1 complex and that produced a functional inhibition of Kv1.1/Kvβ1 channel inactivation. We demonstrated that this compound reduced the sustained repetitive firing in hippocampal neurons and was able to abolish the development of in vitro epileptiform activity. Conclusions This study describes a rational drug discovery approach for the identification of novel ligands that inhibit Kv1.1 channel inactivation and provides pharmacological evidence that such a mechanism translates into physiological effects by reducing in vitro epileptiform activity.

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“…There is some inconsistency in the reports after levetiracetam intake (also a ligand to the presynaptic vesicle protein SV2A), with some studies reporting an increase in motor threshold (Premoli, Costantini, et al, ; Solinas, Lee, & Reutens, ), while others reported no change (Heidegger, Krakow, & Ziemann, ). The slight increase in motor threshold after BRV intake reported here may relate to a secondary mode of action of BRV in blocking VGSCs (Niespodziany et al, ).…”

Section: Discussionmentioning

confidence: 71%

Effects of antiepileptic drugs on cortical excitability in humans: A TMS‐EMG and TMS‐EEG study

Darmani

Bergmann

Zipser

et al. 2018

Human Brain Mapping

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Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS‐evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage‐gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma‐aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double‐blinded randomized placebo‐controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco‐physiological characterization of TEPs will facilitate utilization of TMS‐EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.

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Brivaracetam Differentially Affects Voltage‐Gated Sodium Currents Without Impairing Sustained Repetitive Firing in Neurons

Cited by 42 publications

References 35 publications

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity

Effects of antiepileptic drugs on cortical excitability in humans: A TMS‐EMG and TMS‐EEG study

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