Separation of antiepileptogenic and antiseizure effects of levetiracetam in the spontaneously epileptic rat (SER).
OBJECTIVE
The long-lasting antiseizure effects of levetiracetam (LEV) have been observed in the spontaneously epileptic rat (SER) that expresses both tonic and absence-like seizures. Furthermore, the antiepileptogenic effects of LEV in addition to antiseizure effects have been reported in the amygdala-kindling model in rats. This suggests that the long-lasting seizure protection of LEV may be at least partly due to its antiepileptogenic effects. Therefore this study aimed to differentiate the antiseizure and potential antiepileptogenic effects of LEV by administering LEV continuously to SERs before the appearance of any seizure expression.


METHODS
LEV was administered to the SERs at 80 mg/kg/day (i.p.) from postnatal weeks 5 to 8. The period of observation for tonic convulsions was from postnatal week 5 to 13. Absence-like seizures were recorded by using conventional EEG in weeks 12 and 13.


RESULTS
After age 7-8 weeks, SERs exhibit spontaneous tonic convulsions. Development of tonic convulsions was significantly inhibited in the LEV group, compared with the control group, by the middle of week 9. A significant reduction of tonic convulsions also was observed in the LEV group until week 13 (5 weeks after termination of the administration). In week 12, the absence-like seizures were significantly lower in the LEV group, compared with the control group.


CONCLUSIONS
This study demonstrates a significant inhibition of seizures after prolonged treatment with LEV before the developmental expression of seizure activity in SERs. This effect is suggested to be due to an antiepileptogenic effect and not an antiseizure effect of LEV, because the half-life of the drug in plasma is short (2-3 h in rats) after single and long-term administration. Furthermore, the inhibition of seizure expression in SERs was still apparent 5 weeks after termination of LEV treatment. These results further suggest that LEV possesses not only antiseizure effects but also antiepileptogenic properties.
Yan
Hai-Dun
HD
Department of Pharmacology, Hiroshima University School of Medicine, Hiroshima, Japan.
Ji-qun
Cai
C
Ishihara
Kumatoshi
K
Nagayama
Takashi
T
Serikawa
Tadao
T
Sasa
Masashi
M
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000706:statistics & numerical data; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology; D006624:Hippocampus / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control*
D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam