Electrophysiological, neurochemical and regional effects of levetiracetam in the rat pilocarpine model of temporal lobe epilepsy.
This study compared levetiracetam (Keppra) with reference antiepileptic drugs (AEDs) in the rat pilocarpine model of temporal lobe epilepsy. Electroencephalogram (EEG) recordings showed that i.p. administration of valproate (300 mg/kg), phenobarbital (5 mg/kg) and clonazepam (0.5 mg/kg) all significantly delayed the appearance of the first epileptic spike discharge in hippocampus as well as synchronous epileptiform activity in hippocampus and cortex. In contrast, i.p. administration of levetiracetam (17 mg/kg) only significantly delayed the appearance of the latter. This was corroborated by findings showing that i.p. administration of levetiracetam (17 mg/kg) significantly opposed pilocarpine-induced increases in the amplitude of the orthodromic population spike in the hippocampal CA3 area of urethane-anaesthetised rats, while valproate (200 mg/kg), phenobarbital (10 mg/kg) and clonazepam (1 mg/kg) had no effect. Pre-treatment i.p. with phenobarbital (10 mg/kg) and clonazepam (0.5 mg/kg) significantly reversed seizure-induced changes in aspartate and GABA concentrations while valproate (300 mg/kg) significantly reduced aspartate concentrations further. In contrast, levetiracetam (34 mg/kg) significantly counteracted all seizure-induced alterations in amino acid concentrations. Midazolam induced significant seizure protection after microinjection into substantia nigra pars reticulata (SNR, 50 nmol), nucleus accumbens (NA, 25 nmol) and caudate putamen (CP, 25 nmol), whereas phenytoin (50 nmol) only showed significant seizure protection after injection into the latter area. Levetiracetam differed by significant seizure protection after injection into SNR (1,000 nmol) and NA (3,000 nmol). These results suggest that levetiracetam is distinct from other AEDs by its ability to selectively suppress synchronisation of neuronal spike and burst firing in hippocampus.
Klitgaard
Henrik
H
UCB S.A. Pharma Sector, Preclinical CNS Research, Braine-l'Alleud, Belgium. henrik.klitgaard@ucb-group.com
Matagne
Alain
A
Grimee
Renee
R
Vanneste-Goemaere
Jocelyne
J
Margineanu
Doru-Georg
DG
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000378:metabolism; D002998:Clonazepam / Q000008:administration & dosage / Q000627:therapeutic use; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D000077287:Levetiracetam; D008297:Male; D008845:Microinjections; D010634:Phenobarbital / Q000008:administration & dosage / Q000627:therapeutic use; D010862:Pilocarpine; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D010862:Pilocarpine; D001224:Aspartic Acid; D000077287:Levetiracetam; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D014635:Valproic Acid; D010634:Phenobarbital; D010889:Piracetam