Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Epilepsy research, 2010-01, Vol.88 (1), p.46-54

Ort / Verlag

Kidlington: Elsevier B.V

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• Summary Brivaracetam (ucb 34714; BRV), a new antiepileptic drug (AED) candidate, is a pyrrolidone derivative displaying a markedly higher affinity than levetiracetam (LEV; Keppra® ) to the synaptic vesicle protein SV2A, shown to be the brain-specific binding site of LEV. The higher affinity for SV2A correlates significant antiepileptic activity in animal epilepsy models in vitro and in vivo . Since many AEDs act upon inhibiting neuronal Na+ currents, this study explored putative activity of BRV on the properties of these currents. Voltage-activated Na+ currents were recorded by whole-cell patch-clamp on neuronal somas of rat neocortical neurons, grown in dissociated cell culture for up to 12 days. BRV, dissolved at the desired final concentration (between 0.2 μM and 1 mM) was applied by a multi-barrel pipette system near the soma of the recorded neuron. BRV produced a concentration-dependent inhibition of voltage-dependent Na+ currents with IC50 values of 41 μM at the holding potential of −100 mV, and of 6.5 μM at the holding potential of −60 mV. The voltage-dependence of activation and the kinetics of fast inactivation were not modified in the presence of BRV (30 μM). Conversely, the recovery from fast inactivation was significantly slower and the voltage of half-maximal inactivation was shifted toward hyperpolarized value after BRV perfusion in a concentration-dependent manner. Furthermore, BRV (30 μM) induced a significant use-dependent block at 50 Hz stimulation frequency. These results indicate that BRV is able to modulate the voltage-activated Na+ inflow in cortical neurons, which conceivably might contribute to the antiepileptic activity of this drug.