Improvement by nefiracetam of beta-amyloid-(1-42)-induced learning and memory impairments in rats.
1. We have previously demonstrated that continuous i.c.v. infusion of amyloid beta-peptide (A beta), the major constituent of senile plaques in the brains of patients with Alzheimer's disease, results in learning and memory deficits in rats. 2. In the present study, we investigated the effects of nefiracetam [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384] on A beta-(1-42)-induced learning and memory deficits in rats. 3. In the A beta-(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 significantly impaired as compared with A beta-(40-1)-infused control rats. 4. Nefiracetam, at a dose range of 1-10 mg kg(-1), improved learning and memory deficits in the A beta-(1-42)-infused rats when it was administered p.o. 1 h before the behavioural tests. 5. Nefiracetam at a dose of 3 mg kg(-1) p.o. increased the activity of choline acetyltransferase in the hippocampus of A beta-(1-42)-infused rats. 6. Nefiracetam increased dopamine turnover in the cerebral cortex and striatum of A beta-(1-42)-infused rats, but failed to affect the noradrenaline, serotonin and 5-hydroxyindoleacetic acid content. 7. These results suggest that nefiracetam may be useful for the treatment of patients with Alzheimer's disease.
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.
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K
Yamada
T
T
Tanaka
T
T
Mamiya
T
T
Shiotani
T
T
Kameyama
T
T
Nabeshima
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006719:Homovanillic Acid / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D009043:Motor Activity / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D015306:Biogenic Monoamines; D010446:Peptide Fragments; D011619:Psychotropic Drugs; D011760:Pyrrolidinones; D015102:3,4-Dihydroxyphenylacetic Acid; C058876:nefiracetam; D002795:Choline O-Acetyltransferase; D004298:Dopamine; D006719:Homovanillic Acid