Proepileptic phenotype of SV2A-deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam.
OBJECTIVE
Synaptic vesicle protein 2A (SV2A) constitutes a distinct binding site for an antiepileptic drug levetiracetam (Keppra). In the present study we characterized SV2A (+/-) heterozygous mice in several seizure models and tested if the anticonvulsant efficacy of levetiracetam is reduced in these mice.


METHODS
Seizure thresholds of male SV2A (+/-) mice and their wild-type littermates were assessed in pilocarpine (i.p.), kainic acid (s.c.), pentylenetetrazol (i.v.), 6-Hz and maximal electroshock models. Kindling development was compared in amygdala and corneal kindling models. Ex vivo binding of levetiracetam to SV2A was also performed.


RESULTS
Long-term electroencephalography (EEG) monitoring and behavioral observations of SV2A (+/-) mice did not reveal any spontaneous seizure activity. However, a reduced seizure threshold of SV2A (+/-) mice was observed in pilocarpine, kainic acid, pentylenetetrazol, and 6-Hz models, but not in maximal electroshock seizure model. Accelerated epileptogenesis development was also demonstrated in amygdala and corneal kindling models. Anticonvulsant efficacy of levetiracetam, defined as its ability to increase seizure threshold for 6 Hz electrical stimulation, was significantly reduced (approx. 50%) in the SV2A (+/-) mice, consistently with reduced binding to SV2A in these mice. In contrast, valproate produced the same anticonvulsant effect in both SV2A (+/+) and SV2A (+/-) mice.


CONCLUSIONS
The present results evidence that SV2A is involved in mediation of the in vivo anticonvulsant activity of levetiracetam, in accordance with its previously proposed mechanism of action. Furthermore, the present data also indicate that even partial SV2A deficiency may lead to increased seizure vulnerability and accelerated epileptogenesis.
Kaminski
Rafal M
RM
UCB Pharma S.A., CNS Research, B-1420 Braine-l'Alleud, Belgium. rafal.kaminski@ucb.com
Gillard
Michel
M
Leclercq
Karine
K
Hanon
Etienne
E
Lorent
Geneviève
G
Dassesse
Donald
D
Matagne
Alain
A
Klitgaard
Henrik
H
D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004597:Electroshock / Q000706:statistics & numerical data; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D007608:Kainic Acid; D007696:Kindling, Neurologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000077287:Levetiracetam; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D010433:Pentylenetetrazole / Q000494:pharmacology; D010597:Pharmacogenetics; D010641:Phenotype; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology
D000927:Anticonvulsants; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C489614:Sv2a protein, mouse; D000077287:Levetiracetam; D007608:Kainic Acid; D010433:Pentylenetetrazole; D010889:Piracetam