DM-9384, a new cognition-enhancing agent, increases the turnover of components of the GABAergic system in the rat cerebral cortex.
DM-9384 (nefiracetam) (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide), a pyrrolidone derivative (or a cyclic derivative of gamma-aminobutyric acid (GABA)), is a newly developed nootropic (or cognition-enhancing) agent. In the present study, we examined the biochemical effect of DM-9384 on GABAergic neurons in adult rat brains. DM-9384, when administered orally at a daily dose of 10 mg/kg for 7 days, significantly increased GABA turnover and glutamic acid decarboxylase activity in the cortex and hippocampus, and stimulated Na(+)-dependent high-affinity GABA uptake in cortical synaptosomes. In in vitro experiments, the K(+)-evoked release of [14C]GABA from cortical slices was markedly increased by low concentrations (10(-8), 10(-9) M) of DM-9384. The binding of GABAA and benzodiazepine to their receptors in the brain was not affected by DM-9384 (10(-10)-10(-3) M). The results suggest that DM-9384 increases the turnover of components of the GABAergic system by influencing presynaptic sites rather than postsynaptic sites.
Watabe
S
S
Exploratory Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Yamaguchi
H
H
Ashida
S
S
D000284:Administration, Oral; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002491:Central Nervous System Agents; D011760:Pyrrolidinones; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C058876:nefiracetam; D005680:gamma-Aminobutyric Acid; D012964:Sodium; D005968:Glutamate Decarboxylase