Dm-9384, a Pyrrolidone Derivative, Ameliorates Basal Forebrain Lesion-Induced Amnesia and Inhibits Cycloheximide-Induced Decrease in the Number of GABA and Acetylcholine Receptors

Kameyama, Tsutomu; Nabeshima, Toshitaka; Tohyama, Keiko; Ogawa, Shin-ichi; Murase, Kiyoko; Ishihara, Seiichi

doi:10.1007/978-1-4684-5847-3_75

Cited by 6 publications

(2 citation statements)

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“…Treatments such as AF64A, Cycloheximide, and basal forebrain lesions that a¤ected the cholinergic neurotransmitter system and induced behavioral amnesia could be ameliorated by neÞracetam (Hara and Ogawa 1990;Kameyama et al 1990;Nabeshima et al 1991a,b;Shiotani et al 1992;Abe et al 1994). Of particular interest for the present research are the experiments with neÞracetam and scopolamine-induced dysfunction of the cholinergic neurotransmitter system.…”

Section: Introductionmentioning

confidence: 92%

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam

Woodruff-Pak

Hinchliffe

1997

Psychopharmacology

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Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer's disease (AD). Nicotinic cholinergic receptors are lost in AD, and nicotinic as well as muscarinic cholinergic receptors are involved in the modulation of eyeblink conditioning. Experiments were carried out using young rabbits to examine the effect of nefiracetam on cholinergic antagonists to nicotinic (mecamylamine) and muscarinic (scopolamine) receptors. Rabbits were tested for 15 days in the 750 ms delay eyeblink classical conditioning paradigm in paired and explicitly unpaired conditions. Nefiracetam at a dose of 15 mg/kg significantly ameliorated the effects of 0.5 mg/kg mecamylamine, and nefiracetam at a dose of 10 mg/kg significantly ameliorated the effect of 1.5 mg/kg scopolamine. The vehicle alone and nefiracetam alone groups performed similarly to the groups treated with mecamylamine or scopolamine and nefiracetam. Reversal by nefiracetam of a nicotinic as well as a muscarinic cholinergic antagonist indicates that the drug may affect deficits specific to AD.

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Section: Introductionmentioning

confidence: 92%

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam

Woodruff-Pak

Hinchliffe

1997

Psychopharmacology

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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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Piracetam and other structurally related nootropics

Gouliaev

Senning

1994

Brain Research Reviews

299

192

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Dm-9384, a Pyrrolidone Derivative, Ameliorates Basal Forebrain Lesion-Induced Amnesia and Inhibits Cycloheximide-Induced Decrease in the Number of GABA and Acetylcholine Receptors

Cited by 6 publications

References 1 publication

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam

Mecamylamine- or scopolamine-induced learning impairment: ameliorated by nefiracetam

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

Piracetam and other structurally related nootropics

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