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Procognitive effect of AC-3933 in aged mice, and synergistic effect of combination with donepezil in scopolamine-treated mice.

Abstract
We have previously reported that AC-3933, a newly developed benzodiazepine receptor partial inverse agonist, facilitates acetylcholine release in the hippocampus and ameliorates scopolamine-induced memory deficits in rats. To further confirm the procognitive effect of AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of AC-3933 and donepezil, a cholinesterase inhibitor, on scopolamine-induced memory impairment in mice. In aged mice, oral administration of AC-3933 at doses of 0.05-0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In scopolamine-treated mice, both AC-3933 and donepezil significantly ameliorated memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of AC-3933, but not that of donepezil, on scopolamine-induced memory impairment was antagonized by flumazenil, a benzodiazepine receptor antagonist, indicating that the procognitive action of AC-3933 arises via a mechanism different from that of donepezil. Co-administration of donepezil at the suboptimal dose of 3 mg/kg with AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated scopolamine-induced memory impairment, suggesting that AC-3933 potentiates the effect of donepezil on memory impairment induced by cholinergic hypofunction. These findings indicate that AC-3933 not only has good potential as a cognitive enhancer by itself, but also is useful as a concomitant drug for the treatment of Alzheimer׳s disease.
AuthorsTakashi Hashimoto, Yuki Hatayama, Keiko Nakamichi, Naoyuki Yoshida
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 745 Pg. 123-8 (Dec 15 2014) ISSN: 1879-0712 [Electronic] Netherlands
PMID25446931 (Publication Type: Journal Article)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine
  • GABA-A Receptor Agonists
  • Indans
  • Naphthyridines
  • Nootropic Agents
  • Oxadiazoles
  • Piperidines
  • Flumazenil
  • Donepezil
  • Scopolamine
Topics
  • Aging (psychology)
  • Animals
  • Donepezil
  • Drug Synergism
  • Flumazenil (administration & dosage)
  • GABA-A Receptor Agonists (administration & dosage)
  • Indans (administration & dosage)
  • Male
  • Maze Learning (drug effects)
  • Memory Disorders (chemically induced, drug therapy, psychology)
  • Mice
  • Mice, Inbred C57BL
  • Naphthyridines (administration & dosage)
  • Nootropic Agents (administration & dosage)
  • Oxadiazoles (administration & dosage)
  • Piperidines (administration & dosage)
  • Rats
  • Scopolamine (toxicity)

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