TY - JOUR
T1 - Seletracetam (ucb 44212) inhibits high-voltage-activated Ca2+ currents and intracellular Ca2+ increase in rat cortical neurons in vitro
AU - Martella, Giuseppina
AU - Bonsi, Paola
AU - Sciamanna, Giuseppe
AU - Platania, Paola
AU - Madeo, Graziella
AU - Tassone, Annalisa
AU - Cuomo, Dario
AU - Pisani, Antonio
PY - 2009/4
Y1 - 2009/4
N2 - 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 Ca2+ concentration [Ca2+]i. Moreover, the involvement of high-voltage activated Ca2+ currents (HVACCs) was investigated by means of patch-clamp recordings from acutely dissociated pyramidal neurons. Results: SEL significantly reduced both the duration of PDSs (IC50 = 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 [Ca2+]i rise accompanying PDSs (up to 75% of control values, IC50 = 345.0 ± 15.0 nm). 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 Ca2+ 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 [Ca2+]i influx might be relevant for its antiepileptic efficacy and, more broadly, for pathologic processes involving neuronal [Ca 2+]i overload.
AB - 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 Ca2+ concentration [Ca2+]i. Moreover, the involvement of high-voltage activated Ca2+ currents (HVACCs) was investigated by means of patch-clamp recordings from acutely dissociated pyramidal neurons. Results: SEL significantly reduced both the duration of PDSs (IC50 = 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 [Ca2+]i rise accompanying PDSs (up to 75% of control values, IC50 = 345.0 ± 15.0 nm). 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 Ca2+ 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 [Ca2+]i influx might be relevant for its antiepileptic efficacy and, more broadly, for pathologic processes involving neuronal [Ca 2+]i overload.
KW - Acutely dissociated neuron
KW - Calcium imaging
KW - Epileptiform activity
KW - Levetiracetam
KW - Pyramidal neuron
KW - Slice
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UR - http://www.scopus.com/inward/citedby.url?scp=64049087839&partnerID=8YFLogxK
U2 - 10.1111/j.1528-1167.2008.01915.x
DO - 10.1111/j.1528-1167.2008.01915.x
M3 - Article
C2 - 19055493
AN - SCOPUS:64049087839
VL - 50
SP - 702
EP - 710
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 4
ER -