title: AC-3933, a benzodiazepine partial inverse agonist, improves memory performance in MK-801-induced amnesia mouse model.
abstract: AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor.
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: Yoshihiro
authors.initials: Y
authors.lastname: Iwamura
mesh_terms: D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy / Q000523:psychology*; D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: C483032:5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine; D009287:Naphthyridines; D010069:Oxadiazoles; D011963:Receptors, GABA-A; D016291:Dizocilpine Maleate
keywords: Benzodiazepine receptor; Cognition; Flumazenil; Inverse agonist; MK-801; Object location test; Y-maze test