title: Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats.
abstract: Nefiracetam is a novel pyrrolidone-type nootropic agent, and it has been reported to possess a potential for antiepileptic therapy as well as cognition-enhancing effects. We investigated the anticonvulsant and neuroprotective effects of nefiracetam in kainic acid-induced seizures of rats, compared with levetiracetam and standard antiepileptic drugs. Subcutaneous injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas). Nefiracetam (25, 50 and 100 mg/kg po) had no effect on the behavioral seizures and dose-dependently inhibited the hippocampal damage. In contrast, levetiracetam, a pyrrolidone-type antiepileptic drug, inhibited neither. Valproic acid and ethosuximide prevented the hippocampal damage without attenuating the behavioral seizures as nefiracetam. Zonisamide and phenytoin did not inhibit the behavioral seizures, while zonisamide enhanced the hippocampal damage and phenytoin increased the lethality rate. Carbamazepine inhibited the behavioral seizures at 50 mg/kg and enhanced that at 100 mg/kg, and it completely inhibited the hippocampal damage at both doses. We have previously reported that anticonvulsant spectrum of nefiracetam paralleled that of zonisamide, phenytoin or carbamazepine in standard screening models. However, the pharmacological profile of nefiracetam was closer to valproic acid or ethosuximide than that of zonisamide, phenytoin or carbamazepine in this study. These results suggest that anticonvulsant spectrum and mechanism of nefiracetam are distinct from those of standard antiepileptic drugs, and nefiracetam possesses a neuroprotective effect that is unrelated to seizure inhibition.
authors.affiliation: New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. kitanpms@daiichipharm.co.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kitano
authors.forename: Chika
authors.initials: C
authors.lastname: Komiyama
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Makino
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takasuna
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satoh
authors.forename: Takashi
authors.initials: T
authors.lastname: Aoki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Akira
authors.initials: A
authors.lastname: Takazawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007608:Kainic Acid; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013223:Statistics as Topic; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D018696:Neuroprotective Agents; D011760:Pyrrolidinones; C058876:nefiracetam; D007608:Kainic Acid