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


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.
Martella
Giuseppina
G
Department of Neuroscience, University of Rome Tor Vergata, and Fondazione Santa Lucia, IRCCS, Rome, Italy.
Bonsi
Paola
P
Sciamanna
Giuseppe
G
Platania
Paola
P
Madeo
Graziella
G
Tassone
Annalisa
A
Cuomo
Dario
D
Pisani
Antonio
A
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics / Q000379:methods; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D000077287:Levetiracetam; D008274:Magnesium / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D019579:Neocortex / Q000166:cytology*; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018756:GABA Antagonists; D026902:Potassium Channel Blockers; D011760:Pyrrolidinones; C518915:Seletracetam; D000077287:Levetiracetam; D015761:4-Aminopyridine; D008274:Magnesium; D002118:Calcium; D001640:Bicuculline; D010889:Piracetam