Effects of nefiracetam on amnesia animal models with neuronal dysfunctions.
The effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide (nefiracetam; DM-9384), on learning and memory in several amnesia animal models with neuronal dysfunctions were investigated. Nefiracetam improved scopolamine-, bicuculline-, picrotoxin-, ethanol-, chlordiazepoxide- and cycloheximide-induced amnesia. Anti-amnesic action of nefiracetam on scopolamine model was antagonized by nifedipine and flunarizine, but not by diltiazem. Repeated administration of nefiracetam to AF64A-treated animals improved impairment of learning and memory as well as the alterations in cholinergic and monoaminergic neurotransmitters in the hippocampus. Basal forebrain (BF) lesioned rats induced by excitotoxin or by thermal coagulation showed impairment of learning accompanied by a marked reduction in choline acetyltransferase (ChAT) and acetylcholine esterase activities. Nefiracetam improved the learning deficit of the BF-lesioned rats. Nefiracetam also improved the carbon monoxide-induced delayed and acute amnesia. Nefiracetam stimulated acetylcholine release in the frontal cortex. Repeated administration of nefiracetam increased ChAT activity, gamma-aminobutyric acid (GABA) turnover and glutamic acid decarboxylase activity, and facilitated the Na(+)-dependent high-affinity GABA uptake. Nefiracetam activated the high voltage-activated (N/L-type) Ca2+ channel. The dose-response curves of nefiracetam were bell-shaped in both behavioral and biochemical studies. Therefore, it is suggested that nefiracetam improves the dysfunction of cholinergic, GABAergic and/or monoaminergic neuronal function by acting at Ca2+ channel and enhancing the release of neurotransmitters, and modifies impairment of memory processes induced by drugs and hypoxia.
Hiramatsu
M
M
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
Shiotani
T
T
Kameyama
T
T
Nabeshima
T
T
D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity; D001362:Avoidance Learning / Q000187:drug effects; D001569:Benzodiazepines; D002492:Central Nervous System Depressants / Q000633:toxicity; D018680:Cholinergic Antagonists / Q000494:pharmacology; D000431:Ethanol / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009422:Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D018697:Nootropic Agents / Q000627:therapeutic use*; D011500:Protein Synthesis Inhibitors / Q000633:toxicity; D011760:Pyrrolidinones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects
D014151:Anti-Anxiety Agents; D002492:Central Nervous System Depressants; D018680:Cholinergic Antagonists; D018691:Excitatory Amino Acid Antagonists; D018697:Nootropic Agents; D011500:Protein Synthesis Inhibitors; D011760:Pyrrolidinones; D001569:Benzodiazepines; C058876:nefiracetam; D000431:Ethanol