Effects of Nefiracetam, a Novel Pyrrolidone‐type Nootropic Agent, on the Amygdala‐kindled Seizures in Rats

Abstract

Summary:Purpose: Nefiracetam (NEF) is a novel pyrrolidonetype nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the effects of NEF in amygdala-kindled seizures and its potential for antiepileptic therapy.Methods: Effects of NEF on fully amygdala-kindled seizures and development of amygdala-kindled seizures were investigated in rats and compared with those of levetiracetam (LEV), a pyrrolidone-type antiepileptic drug (AED).Results: In fully amygdala-kindled rats, NEF (25, 50, and 100 mg/kg, p.o.) decreased afterdischarge induction, afterdischarge duration, seizure stage, and motor seizure duration in a dosedependent manner. LEV (25, 50, and 100 mg/kg, p.o.) had no effects on afterdischarge induction and slightly decreased afterdischarge duration, whereas it markedly decreased seizure stage and motor seizure duration. In contrast to the results in fully amygdala-kindled rats, NEF (25 and 50 mg/kg/day, p.o.) had few or no effects on the development of amygdala-kindled seizures. As well as fully amygdala-kindled seizures, LEV (50 mg/kg/day, p.o.) markedly inhibited the development of behavioral seizures without reducing daily afterdischarge duration.Conclusions: Although NEF possesses potent anticonvulsant effects on fully amygdala-kindled seizures, it has few or no effects on the development of amygdala-kindled seizures. LEV shows marked anticonvulsant effects on both phases of kindling. In fully amygdala-kindled rats, NEF inhibits both electroencephalographic and behavioral seizures, whereas LEV inhibits only behavioral seizures. This double dissociation suggests that NEF has a distinct anticonvulsant spectrum and mechanisms from those of LEV. Key Words: NefiracetamLevetiracetam-Antiepileptic-Amygdala-Kindling. Nefiracetam [NEF; N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384] is a novel pyrrolidone-type nootropic agent (1,2) and possesses cognition-enhancing effects in various animal models (3-6). Electrophysiologic and neurochemical studies have demonstrated that NEF activates N/L-type Ca 2+ channels (7,8), and cholinergic, monoaminergic, and γ -aminobutyric acid (GABA)-ergic systems (9-14).Some pyrrolidone derivatives have been reported to possess anticonvulsant activities (15)(16)(17), and the first pyrrolidone, piracetam, and its ethyl analogue, levetiracetam Accepted May 28, 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: kitanpms@daiichipharm.co.jp (LEV), have been licensed and used in many countries for myoclonus and epilepsy (18)(19)(20). Especially LEV has a unique anticonvulsant profile (21-24), and its excellent efficacy and tolerability have been demonstrated in clinical studies (25)(26)(27). We previously reported that NEF inhibits electroshock-induced seizures in mice and rats (28,29), and it also has been shown to have antico...

Apathy following Stroke

“…39 Nefiracetam is a novel cyclic gamma-aminobutyric compound that has been demonstrated in animal studies to enhance aminergic, glutamatergic, and cholinergic neurotransmission by stimulating alpha-4, beta-2 type neuronal nicotinic acetylcholine receptors. [40][41][42][43][44][45] In addition, nefiracetam increased brain-derived neurotrophic factor expression as well as rCBF and glucose use after sustained cerebral ischemia in rats. 46,47 Robinson et al 48 have conducted a 12-week randomized double-blind, placebo-controlled trial assessing the efficacy of nefiracetam for treatment of poststroke depression.…”

Brivaracetam attenuates pain behaviors in a murine model of neuropathic pain

“…LEV, BRV, and piracetam are known to bind to SV2A, 27,28,79 but to our knowledge, SV2A binding has not been demonstrated for dimiracetam and nefiracetam, 80 although the latter is reported to have antiseizure properties. 81 At present, a unifying molecular mechanism is lacking to explain how such structurally diverse molecules as the racetams depicted in Figure 1 can be effective in neuropathic pain.…”

Human Fetal Brain-Derived Neural Stem/Progenitor Cells Grafted into the Adult Epileptic Brain Restrain Seizures in Rat Models of Temporal Lobe Epilepsy

“…After a recovery period of 1 week, afterdischarge threshold (ADT) was determined by passing constant pulse trains (1 ms, biphasic rectangular wave, 50 Hz for 1 s). The initial current of 10 µA was delivered, increasing the current intensity in steps of 10 µA (to a maximum of 150 µA), with intervals of 1 min between current deliveries until an afterdischarge (AD) was seen, defined as poststimulus electroencephalogram (EEG) spikes with a frequency of greater than 1 Hz and an amplitude at least two times greater that of the pre-stimulus recording [32]. The rats were stimulated at the ADT intensity twice daily until five consecutive stage 5 or higher seizures (according to the additional Racine scale [33]) were elicited: Stage 1, facial movements only; Stage 2, facial movements and head nodding; Stage 3, facial movements, head nodding, and forelimb clonus; Stage 4, facial movements, head nodding, forelimb clonus, and rearing; Stage 5, facial movements, head nodding, forelimb clonus, rearing, and falling; Stage 6, cluster of multiple Stage 5 seizures; Stage 7, jumping and running seizures; and Stage 8, Stage 7 plus tonic hindlimb extension and tail rigidity, sometimes culminating in death.…”