title: 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.
authors.affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: takashi-hashimoto@ds-pharma.co.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hatayama
authors.affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakamichi
authors.affiliation: Innovative Drug Discovery Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Yoshida
mesh_terms: D000375:Aging / Q000523:psychology*; D000818:Animals; D000077265:Donepezil; D004357:Drug Synergism; D005442:Flumazenil / Q000008:administration & dosage; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage; D007189:Indans / Q000008:administration & dosage*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000008:administration & dosage*; D018697:Nootropic Agents / Q000008:administration & dosage*; D010069:Oxadiazoles / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D012601:Scopolamine / Q000633:toxicity
chemical_list: C483032:5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine; D058785:GABA-A Receptor Agonists; D007189:Indans; D009287:Naphthyridines; D018697:Nootropic Agents; D010069:Oxadiazoles; D010880:Piperidines; D005442:Flumazenil; D000077265:Donepezil; D012601:Scopolamine
keywords: Aged; Benzodiazepine receptor; Cognition; Inverse agonist; Scopolamine