Antiepileptic effects of single and repeated oral administrations of S-312-d, a novel calcium channel antagonist, on tonic convulsions in spontaneously epileptic rats.
We investigated the effects of single and repeated administrations of S-312-d (methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)-thieno-[2,3-b]pyridine-5-carboxylate), a newly synthesized L-type Ca(2+)-channel blocker, on tonic convulsions and absence-like seizures in the spontaneously epileptic rat (SER: zi/zi, tm/tm), a genetically based animal model of human epilepsy. Single oral administrations of S-312-d dose-dependently inhibited tonic convulsions and the effects lasted for more than 2 h, although they did not attenuate the absence-like seizures. We also examined the effects of repeated administrations of S-312-d at 1 mg/kg once a day for 4 days on SER. A significant decrease in the number and total duration of tonic convulsions was observed 45 and 75 min after the first administration of the drug, respectively. The effects lasted for 24 h without changes in the background EEG or blood pressure. This inhibitory effect on the tonic convulsions was gradually strengthened by subsequent daily administrations of S-312-d and lasted for 3 days after the cessation of drug treatment. In contrast, the repeated treatment with S-312-d did not influence absence-like seizures of SER. These results suggest that S-312-d is a candidate drug that has antiepileptic effects against the convulsive seizures in human epilepsy.
Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Kasumi, Minami, Hiroshima 734-8551, Japan.
Taku
T
Amano
Zhu
Z
Aihua
Hiroaki
H
Matsubayashi
Takahiro
T
Seki
Tadao
T
Serikawa
Masashi
M
Sasa
Norio
N
Sakai
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000188:drug therapy / Q000503:physiopathology; D004829:Epilepsy, Generalized / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D008297:Male; D051381:Rats; D013997:Time Factors
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C059447:S 312