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Seletracetam (ucb 44212) inhibits high‐voltage–activated Ca 2+ currents and intracellular Ca 2+ increase in rat cortical neurons in vitro
Author(s) -
Martella Giuseppina,
Bonsi Paola,
Sciamanna Giuseppe,
Platania Paola,
Madeo Graziella,
Tassone Annalisa,
Cuomo Dario,
Pisani Antonio
Publication year - 2009
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2008.01915.x
Subject(s) - chemistry , depolarization , intracellular , voltage dependent calcium channel , calcium , in vitro , patch clamp , inhibitory postsynaptic potential , electrophysiology , calcium in biology , epilepsy , biophysics , neuroscience , medicine , receptor , biochemistry , biology , organic chemistry
Summary Purpose: 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. Methods: 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. Results: SEL significantly reduced both the duration of PDSs (IC 50 = 241.0 ± 21.7 n m ) as well as the number of action potentials per PDS (IC 50 = 82.7 ± 9.7 n m ). In addition, SEL largely decreased the [Ca 2+ ] i rise accompanying PDSs (up to 75% of control values, IC 50 = 345.0 ± 15.0 n m ). Furthermore, SEL significantly reduced HVACCs in pyramidal neurons. This effect was mimicked by ω‐conotoxin GVIA and, to a lesser extent, by ω‐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. Conclusions: 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.