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

• Published in: British journal of pharmacology 1999-01, Vol.126 (1), p.235-244
• Main Authors: Yamada, Kiyofumi, Tanaka, Tomoko, Mamiya, Takayoshi, Shiotani, Tadashi, Kameyama, Tsutomu, Nabeshima, Toshitaka
• Format: Article
• Language: English
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Alzheimer's disease; Amyloid beta-Peptides - pharmacology; amyloid β‐peptide; Animals; Avoidance Learning - drug effects; Biogenic Monoamines - metabolism; Biological and medical sciences; Choline O-Acetyltransferase - drug effects; Choline O-Acetyltransferase - metabolism; Corpus Striatum - drug effects; Corpus Striatum - enzymology; Dopamine - metabolism; Frontal Lobe - drug effects; Frontal Lobe - enzymology; Hippocampus - drug effects; Hippocampus - enzymology; Homovanillic Acid - metabolism; Learning - drug effects; Learning Disabilities - chemically induced; Learning Disabilities - drug therapy; Male; Maze Learning - drug effects; Medical sciences; Memory Disorders - chemically induced; Memory Disorders - drug therapy; Motor Activity - drug effects; nefiracetam; nefiracetam (DM‐9384); Neuropharmacology; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Psychotropic Drugs - pharmacology; Psychotropic Drugs - therapeutic use; Pyrrolidinones - pharmacology; Pyrrolidinones - therapeutic use; Rats; Rats, Wistar; reference memory; voltage‐sensitive calcium channels; working memory
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0702309

We have previously demonstrated that continuous i.c.v. infusion of amyloid β‐peptide (Aβ), the major constituent of senile plaques in the brains of patients with Alzheimer's disease, results in learning and memory deficits in rats. In the present study, we investigated the effects of nefiracetam [N‐(2,6‐dimethylphenyl)‐2‐(2‐oxo‐1‐pyrrolidinyl) acetamide, DM‐9384] on Aβ‐(1–42)‐induced learning and memory deficits in rats. In the Aβ‐(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 Aβ‐(40–1)‐infused control rats. Nefiracetam, at a dose range of 1–10 mg kg−1, improved learning and memory deficits in the Aβ‐(1–42)‐infused rats when it was administered p.o. 1 h before the behavioural tests. Nefiracetam at a dose of 3 mg kg−1 p.o. increased the activity of choline acetyltransferase in the hippocampus of Aβ‐(1–42)‐infused rats. Nefiracetam increased dopamine turnover in the cerebral cortex and striatum of Aβ‐(1–42)‐infused rats, but failed to affect the noradrenaline, serotonin and 5‐hydroxyindoleacetic acid content. These results suggest that nefiracetam may be useful for the treatment of patients with Alzheimer's disease. British Journal of Pharmacology (1999) 126, 235–244; doi:10.1038/sj.bjp.0702309