Effects of nefiracetam, DM-9384 on amnesia and decrease in cholineacetyltransferase activity induced by cycloheximide

Shiotani, Tadashi; Tohyama, Keiko; Murase, Kiyoko; Ishihara, Seiichi; Kameyama, Tsutomu; Yamasaki, Terukiyo; Hatanaka, Satoshi; Kojima, Hiroshi; Takasu, Y.; Nabeshima, Toshitaka

doi:10.1007/bf01250792

Cited by 7 publications

(6 citation statements)

References 32 publications

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“…In addition, nefiracetam modulates GABA A ( Huang et al ., 1996 ) or nicotinic ACh receptor currents ( Nishizaki et al ., 1998 ), stimulates ChAT and glutamate decarboxylase activities ( Shiotani et al ., 1992 ; Tanaka et al ., 1992 ; Watabe et al ., 1993 ), and muscarinic ACh receptor binding ( Nabeshima et al ., 1991b ). Therefore, these effects may also contribute to the amelioration by nefiracetam of Aβ‐(1–42)‐induced learning and memory deficits.…”

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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“…The reduction of the binding was due to changes in B, , , but not Kd (55). The activity of ChAT in the cerebral cortex was also significantly reduced by cycloheximide (70). Nefiracetam (5 mgkg p.0.)…”

Section: Neuronal Dysfunction In Animal Models Of Neurological Disordersmentioning

confidence: 95%

“…administered 15 min before cycloheximide prevented the decreases in both [3H]QNB and [3H]muscimol binding (55). At a dose of 30 mg/kg, nefiracetam prevented the decrease in ChAT activity in the cerebral cortex (70).…”

Section: Neuronal Dysfunction In Animal Models Of Neurological Disordersmentioning

confidence: 99%

Nefiracetam (DM‐9384): A Novel Antiamnesic Drug

Yamada

Nabeshima

1996

CNS Drug Reviews

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Key Words: Alzheimer's disease-Cognitive enhancer-Learning and memory-Nefiracetam (DM-9384+Nootropics.Senile dementia is classified into two types: cerebrovascular dementia and Alzheimer-type dementia; drug treatment and physiotherapy are employed to maintain and enhance neuronal function that has not degenerated and been lost. Cerebral hemorrhage, infarction, and embolism are considered to be the causes of cerebrovascular dementia. Therefore, drugs that improve cerebral circulation and metabolism, or enhance cerebral neurotransmission, are used for treatment, in the expectation that they can increase cerebral blood flow and oxygen consumption, and thereby' improve brain function.The cause of Alzheimer-type dementia has not yet been elucidated, and there is no specific effective treatment, except for tacrine, a cholinesterase inhibitor, which was approved by the U. S. Food and Drug Administration in September, 1993, after a lengthy debate. Although drugs that affect cerebral circulation and metabolism are used in the treatment of Alzheimer-type dementia, most of these agents are ineffective for the treatment of amnesia, a core symptom of this dementia.In 1982, Giurgea proposed the term "nootropicsyy for drugs with properties that: (i) enhance learning and memory; (ii) facilitate the flow of information between the cerebral hemispheres; (iii) enhance resistance to chemical and physical injuries; and (iv) lack conventional psychological and general cardiovascular pharmacological activity (15). Many compounds that have a pyrrolidone skeleton have been developed as nootropics since the first of these agents, piracetam, was developed.Nefiracetam, a novel pyrrolidone derivative, synthesized by Nattermann in Germany, has been developed as a therapeutic drug for dementia by Daiichi Pharmaceutical Co. Ltd., Japan. Phase I11 clinical trials have been completed with patients showing the sequelae of cerebrovascular disorders, and phase I1 clinical trials have been in

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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: 93%

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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Effects of nefiracetam, DM-9384 on amnesia and decrease in cholineacetyltransferase activity induced by cycloheximide

Cited by 7 publications

References 32 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

Nefiracetam (DM‐9384): A Novel Antiamnesic Drug

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

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