Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy.
Seletracetam is a pyrrolidone derivative with a one-log-unit higher affinity for the synaptic vesicle protein 2A (SV2A) than levetiracetam (Keppra). This study explored its anticonvulsant properties in animal models of epilepsy. Seletracetam reduced both the amplitude and repetitive firing of population spikes induced by a high K(+)/low Ca(2+) concentration fluid (HKLCF) in rat hippocampal slices. The reduction of HKLCF-induced increases in population spike amplitude was particularly pronounced, and occurred at approximately 10 times lower seletracetam concentrations than previously observed for levetiracetam. These invitro data suggest that desynchronisation of epileptiform activity may contribute significantly to the antiepileptic properties of seletracetam. Seletracetam also showed a potent anti-seizure activity in animal models mimicking partial-onset (kindled animals) and generalized epilepsy (audiogenic seizure susceptible mice and genetic absence epilepsy rats from Strasbourg (GAERS)). In amygdala-kindled rats, seletracetam increased the generalized seizure threshold current and decreased the duration of the after-discharge and the seizure severity observed at the after-discharge threshold current, and generally had a much more potent effect than previously observed for levetiracetam. Seletracetam showed no psychomimetic effects and a very high central nervous system (CNS) tolerability in both kindled and GAERS rats, markedly superior to that of levetiracetam and other antiepileptic drugs. These results suggest that seletracetam may represent an effective and very well tolerated broad-spectrum agent for the symptomatic treatment of epilepsy.
Matagne
Alain
A
CNS Research, UCB Pharma SA, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium. Alain.Matagne@UCB.com
Margineanu
Doru-Georg
DG
Potschka
Heidrun
H
Löscher
Wolfgang
W
Michel
Philippe
P
Kenda
Benoit
B
Klitgaard
Henrik
H
D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology
D011760:Pyrrolidinones; C518915:Seletracetam