Nefiracetam enhances acetylcholine outflow from the frontal cortex: in vivo microdialysis study in the rat

Kawajiri, Shinichi; Taniguchi, Keiko; Sakurai, Takeo; Yamasaki, Terukiyo

doi:10.1007/bf01277591

Cited by 15 publications

(5 citation statements)

References 21 publications

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“…Accordingly, it is plausible that nefiracetam ameliorates the Aβ‐(1–42)‐induced learning and memory deficits by activating VSCC, and thereby stimulates release of ACh and dopamine in the brain. Indeed, it has been shown that nefiracetam stimulates the turnover of ACh ( Abe et al ., 1994 ; Kawajiri et al ., 1994 ), dopamine ( Abe et al ., 1992 ; 1994 ) and GABA ( Watabe et al ., 1993 ), as well as ACh release in the frontal cortex ( Sakurai et al ., 1998 ). In the present study, we have demonstrated that nefiracetam can increase dopamine turnover in the cerebral cortex and striatum in the Aβ‐treated rats.…”

Section: Discussionmentioning

confidence: 99%

Improvement by nefiracetam of β‐amyloid‐(1‐42)‐induced learning and memory impairments in rats

Yamada

Tanaka

Mamiya

et al. 1999

British J Pharmacology

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1 We have previously demonstrated that continuous i.c.v. infusion of amyloid b-peptide (Ab), the major constituent of senile plaques in the brains of patients with Alzheimer's disease, results in learning and memory de®cits in rats. 2 In the present study, we investigated the e ects of ne®racetam [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384] on Ab-(1-42)-induced learning and memory de®cits in rats. 3 In the Ab-(1-42)-infused rats, spontaneous alternation behaviour in a Y-maze task, spatial reference and working memory in a water maze task, and retention of passive avoidance learning were signi®cantly impaired as compared with Ab-(40-1)-infused control rats. 4 Ne®racetam, at a dose range of 1 ± 10 mg kg 71 , improved learning and memory de®cits in the Ab-(1-42)-infused rats when it was administered p.o. 1 h before the behavioural tests. 5 Ne®racetam at a dose of 3 mg kg 71 p.o. increased the activity of choline acetyltransferase in the hippocampus of Ab-(1-42)-infused rats. 6 Ne®racetam increased dopamine turnover in the cerebral cortex and striatum of Ab-(1-42)-infused rats, but failed to a ect the noradrenaline, serotonin and 5-hydroxyindoleacetic acid content. 7 These results suggest that ne®racetam may be useful for the treatment of patients with Alzheimer's disease. Keywords: Alzheimer's disease; amyloid b-peptide; ne®racetam (DM-9384); reference memory; voltage-sensitive calcium channels; working memoryAbbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; Ab, amyloid b-peptide; ACh, acetylcholine; AD, Alzheimer's disease; ANOVA, one-way analysis of variance; APP, b-amyloid precursor protein; ChAT, choline acetyltransferase; DOPAC, 3,4-dihydroxyphenylacetic acid; GABA, g-aminobutyric acid; HVA, homovanillic acid; VSCC, voltagesensitive calcium channels IntroductionAlzheimer's disease (AD) is the most common cause of progressive decline of cognitive function in aged humans. The disease is characterized neuropathologically by the presence of numerous senile plaques and neuro®brillary tangles accompanied by neuronal loss. The senile plaques are composed of amyloid b-peptide (Ab), a 40 ± 42 amino acid peptide fragment of the b-amyloid precursor protein (APP) (Kang et al., 1987). Transgenic mice, which overexpress human APP containing the mutations associated with familial AD, develop many of the pathological characterizations associated with AD (Games et al., 1995;Johnson-Wood et al., 1997; Sturchler-Pierrat et al., 1997). Furthermore, Ab is cytotoxic to neurons (Yankner et al., 1990) and renders neurons vulnerable to various insults including excitotoxicity (Koh et al., 1990;Mattson et al., 1992). These previous ®ndings suggest that Ab has a central role in the pathogenesis of AD. We have previously demonstrated that continuous infusion of Ab-(1-40) into the cerebral ventricle of rats results in learning and memory de®cits, suggesting that accumulation of Ab in the brain is related to cognitive impairments in AD . Continuous Ab-(1-40) infusion causes a decrease in choline acetyltransferase ...

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Section: Discussionmentioning

confidence: 99%

Improvement by nefiracetam of β‐amyloid‐(1‐42)‐induced learning and memory impairments in rats

Yamada

Tanaka

Mamiya

et al. 1999

British J Pharmacology

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“…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).…”

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confidence: 99%

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

Kitano

Komiyama²,

Makino³

et al. 2005

Epilepsia

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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...

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“…Nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide), a cyclic derivative of γ-aminobutyric acid (Figure 1), is a potent facilitator of neuronal calcium-channel activity and shows anti-amnesic effects by interacting with GABAergic and AChergic neuronal systems (Kameyama et al 1990 ;Kojima et al 1990 ;Nabeshima et al 1990aNabeshima et al , b, 1991Watabe et al 1993 ;Kawajiri et al 1994 ;Yoshii & Watabe 1994 ;Yoshii et al 1997). This compound is now undergoing clinical trials as a novel neurotransmission-enhancer for the treatment of sequelae of cerebrovascular disorders and Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Nefiracetam metabolism by human liver microsomes: role of cytochrome P450 3A4 and cytochrome P450 1A2 in 5-hydroxynefiracetam formation

Fujimaki

Arai

Nakazawa

et al. 2001

Journal of Pharmacy and Pharmacology

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An in-vitro study was conducted to investigate the metabolism of nefiracetam in human liver microsomes and to identify the enzymes responsible for the metabolism. Nefiracetam was hydroxylated by human liver microsomes to 5-hydroxynefiracetam (5-OHN). Eadie-Hofstee plots for the formation of 5-OHN suggested substrate activation. The kinetic parameters, apparent Km, Vmax, and Hill coefficient, for the formation of 5-OHN by pooled human liver microsomes were 4012 microM, 2.66 nmol min(-1) (mg protein)(-1), and 1.65, respectively. The formation of 5-OHN was significantly correlated with cytochrome P450 (CYP)3A4-mediated testosterone 6beta-hydroxylase activity and dextromethorphan N-demethylase activity. The 5-OHN formation was inhibited (94%) by antibody to human CYP3A4/5. The 5-OHN formation was also inhibited by the CYP3A4 inhibitors ketoconazole and troleandomycin, but not significantly inhibited by several other P450 inhibitors. The microsomes containing cDNA-expressed CYP3A4 formed 5-OHN with sigmoidal kinetics. CYP3A5-containing microsomes did not form 5-OHN. These results indicated that CYP3A, most likely CYP3A4, was the major isozyme responsible for the formation of 5-OHN in human liver microsomes. CYP1A2 and CYP2C19 microsomes were also capable of forming 5-OHN. However, the contribution of CYP1A2 was considered to be relatively minor compared with that of CYP3A4, and the contribution of CYP2C19 was assumed to be negligible, based on the result of the immunoinhibition study and taking into account both the turnover rate by each isozyme and the relative abundance of each isozyme in human liver. We conclude that on average the formation of 5-OHN, the major metabolite of nefiracetam, is principally mediated by CYP3A4 with a relatively minor contribution by CYP1A2.

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Nefiracetam enhances acetylcholine outflow from the frontal cortex: in vivo microdialysis study in the rat

Cited by 15 publications

References 21 publications

Improvement by nefiracetam of β‐amyloid‐(1‐42)‐induced learning and memory impairments in rats

Improvement by nefiracetam of β‐amyloid‐(1‐42)‐induced learning and memory impairments in rats

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

Nefiracetam metabolism by human liver microsomes: role of cytochrome P450 3A4 and cytochrome P450 1A2 in 5-hydroxynefiracetam formation

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