Seletracetam (ucb 44212) inhibits high‐voltage–activated Ca2+ currents and intracellular Ca2+ increase in rat cortical neurons in vitro

Abstract

We analyzed the effects of seletracetam (ucb 44212; SEL), a new antiepileptic drug candidate, in an in vitro model of epileptic activity. The activity of SEL was compared to the effects of levetiracetam (LEV; Keppra), in the same assays. Combined electrophysiologic and microfluorometric recordings were performed from layer V pyramidal neurons in rat cortical slices to study the effects of SEL on the paroxysmal depolarization shifts (PDSs), and the simultaneous elevations of intracellular Ca(2+) concentration [Ca(2+)](i). Moreover, the involvement of high-voltage activated Ca(2+) currents (HVACCs) was investigated by means of patch-clamp recordings from acutely dissociated pyramidal neurons. SEL significantly reduced both the duration of PDSs (IC(50) = 241.0 +/- 21.7 nm) as well as the number of action potentials per PDS (IC(50) = 82.7 +/- 9.7 nm). In addition, SEL largely decreased the [Ca(2+)](i) rise accompanying PDSs (up to 75% of control values, IC(50) = 345.0 +/- 15.0 nm). Furthermore, SEL significantly reduced HVACCs in pyramidal neurons. This effect was mimicked by omega-conotoxin GVIA and, to a lesser extent, by omega-conotoxin MVIIC, blockers of N- and Q-type HVACC, respectively. The combination of these two toxins occluded the action of SEL, suggesting that N-type Ca(2+) channels, and partly Q-type subtypes are preferentially targeted. These results demonstrate a powerful inhibitory effect of SEL on epileptiform events in vitro. SEL showed a higher potency than LEV. The effective limitation of [Ca(2+)](i) influx might be relevant for its antiepileptic efficacy and, more broadly, for pathologic processes involving neuronal [Ca(2+)](i) overload.