Anticonvulsant Properties of the Novel Nootropic Agent Nefiracetam in Seizure Models of Mice and Rats

Abstract

Summary:Purpose: Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognitionenhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy.Methods: The anticonvulsant properties of NEF were investigated in experimental seizure models of mice and rats, compared with levetiracetam (LEV) and other standard antiepileptic drugs [AEDs; zonisamide (ZNS), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), diazepam (DZP), and ethosuximide (ESM)]. With reference to standard programs for evaluating potential AEDs, the study included the traditional maximal electroshock seizure and subcutaneous chemoconvulsant (pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate) seizure tests and two threshold models (the increasing-current electroshock seizure test and intravenous pentylenetetrazole seizure threshold test). Neurotoxic activities were examined with the rotarod test and traction test.Results: NEF inhibited electroshock-induced seizures at nontoxic doses, whereas it had no effect on seizures chemically induced by pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate. The anticonvulsant spectrum of NEF paralleled that of ZNS, PHT, and CBZ. The anticonvulsant efficacy of NEF was comparable with that of ZNS and less potent than that of PHT, CBZ, and DZP. However, the safety margin of NEF was superior to that of ZNS, CBZ, VPA, and DZP. LEV showed only slight anticonvulsant effects in threshold models, and it was not effective in conventional screening models.Conclusions: These results suggest that NEF has distinct anticonvulsant spectrum and mechanisms from those of LEV. NEF is an orally active and safe AED, and it possesses a potential for antiepileptic therapy. Key Words: NefiracetamLevetiracetam-Nootropic-Seizure-Antiepileptic.Cognition-enhancing agents (or nootropics) are drugs used for the treatment of impaired brain function resulting from cerebral deficiencies such as senile dementia or cerebral vascular disorders (1-3). Nefiracetam [NEF; N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM-9384] is a novel pyrrolidone-type nootropic and has been reported to enhance learning acquisition and to improve experimentally induced amnesia in various animal models (4-7). Electrophysiologic and neurochemical studies have demonstrated that NEF activates N/L-type Ca 2+ channels (8,9), and cholinergic, monoaminergic and γ -aminobutyric acid (GABA)ergic systems (10-15).Some pyrrolidone derivatives such as piracetam and oxiracetam have been reported to possess anticonvulsant activities (16) or synergistic effects in combination with antiepileptic drugs (AEDs) (17,18). Piracetam has been Accepted February 6, 2005. Address correspondence and reprint requests to Dr. Y. Kitano at New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. E-mail: kitanpm...

The Neuropharmacology of the Ketogenic Diet

“…Although limited data are available, the profile of zonisamide may be most similar to the ketogenic diet; however, the ketogenic diet protects against seizures induced by bicuculline, whereas zonisamide does not [78]. Zonisamide probably acts through a variety of mechanisms, including via effects on sodium channels and possibly T-type calcium channels, although a complete understanding of its cellular actions is probably still not at hand [4].…”

Effects of Various Antiepileptics on Behavioral and Electroencephalographic Seizures Induced by Maximal Electroshock in Mice

“…1, all the antiepileptics, except ethosuximide, inhibited TE seizure, and the potency of antiepileptics was almost the same as in our previous work (3). It is well recognized that ethosuximide showed no inhibition of TE seizure induced by maximal electroshock in mice and rats (9,12). Next, as shown in Fig.…”

Preclinical antiepileptic actions of selective serotonin reuptake inhibitors—Implications for clinical trial design

“…Generalized tonic–clonic seizures can be induced by systemic injection of the γ‐aminobutyric acid A (GABA A ) receptor antagonist picrotoxin. These seizures are sensitive to several drugs with actions on the GABA system, including valproate, benzodiazepines, felbamate, and vigabatrin, but also to the antiabsence drug ethosuximide, the K + channel opener retigabine, and the Na + channel blocker rufinamide (Löscher & Frey, 1977; Kendall et al., 1981; Swinyard et al., 1986; Rostock et al., 1996; Kitano et al., 2005; White et al., 2008a). Picrotoxin‐induced seizures are, however, not sensitive to numerous Na + and Ca 2+ channel blockers (Rostock et al., 1996; Klitgaard et al., 1998; Michelucci et al., 1998; Tecoma, 1999; Kitano et al., 2005; Stöhr et al., 2007; White et al., 2008a) (Fig.…”