title: Suppression of fully kindled seizure and retardation of kindling acquisition by YM928 in the rat kindling model of epilepsy.
abstract: We investigated the effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, in the rat kindling model of complex partial seizures. YM928 (10 and 30 mg/kg p.o.) markedly suppressed the motor seizures and afterdischarge induced by electrical stimulation of the amygdala at generalized seizure-triggering threshold intensity. YM928 (10 mg/kg p.o.) did not induce apparent abnormal behavior, but did induce sedation at a dose of 30 mg/kg p.o. YM928 (30 mg/kg p.o.) showed a similar anticonvulsant effect at twice the threshold intensity as it did at threshold intensity. Diazepam (10 mg/kg p.o.) and phenobarbital (60 mg/kg p.o.) also exerted anticonvulsant activities. Diazepam (10 mg/kg) showed a similar effect at twice the threshold as at threshold, but the anticonvulsant effect of phenobarbital (60 mg/kg p.o.) was reversed when the stimulus was doubled. When YM928 (10 mg/kg p.o.) was administered 60 min before daily stimulation of the amygdala, the development of kindling seizure was significantly retarded. These results indicate that YM928 has anticonvulsant effects and suppresses kindling acquisition without sedative effects, and may be suitable as an antiepileptic drug for the treatment of complex partial seizures in humans.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd. 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. yamasita@yamanouchi.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamashita
authors.forename: Kazushige
authors.initials: K
authors.lastname: Ohno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inami
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Shishikura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Masamichi
authors.initials: M
authors.lastname: Okada
authors.forename: Tokio
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology*; D004829:Epilepsy, Generalized / Q000503:physiopathology / Q000517:prevention & control; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000517:prevention & control*; D013843:Thiazines / Q000494:pharmacology*
chemical_list: C475769:2-(N-(4-chlorophenyl)-N-methylamino)-4H-pyrido(3,2-e)-1,3-thiazin-4-one; D000927:Anticonvulsants; D011725:Pyridines; D013843:Thiazines; D003975:Diazepam; D010634:Phenobarbital