Effects of a novel cognitive enhancer, spiro[imidazo-[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), on learning impairments induced by amyloid-beta1-40 in the rat.
We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid-beta (Abeta)1-40 produces oxidative stress and cholinergic dysfunction, as well as learning and memory deficits, in rats. In the present study, effects of a newly synthesized azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), were assessed in rats with learning deficits induced by Abeta1-40 or scopolamine. The i.c.v. infusion of Abeta1-40 caused impairments in spontaneous alternation behavior in a Y-maze task, spatial reference and short-term memory in a water-maze task, and retention of passive-avoidance learning. Abeta1-40-infused rats also showed reduction in choline acetyltransferase (ChAT) activity in the medial septum and hippocampus, but not in the basal forebrain and cortex, and a decrease in glutathione S-transferase (GST)-like immunoreactivity in the cortex. Nicotine-stimulated acetylcholine (ACh) release in Abeta1-40-infused rats was lower than that in vehicle-infused rats. Oral administration of ZSET1446 at the dose range of 0.01 to 1 mg/kg ameliorated Abeta1-40-induced learning impairment in Y-maze, water-maze, and passive-avoidance tasks. ZSET1446 reversed the decrease of ChAT activity in the medial septum and hippocampus, GST-like immunoreactivity in the cortex, and nicotine-stimulated ACh release of Abeta1-40-treated rats to the levels of vehicle-infused control rats. Furthermore, 0.001 to 0.1 mg/kg ZSET1446 showed ameliorative effects on learning impairments caused by scopolamine in a passive-avoidance task. These results suggest that ZSET1446 may be a potential candidate for development as a therapeutic agent to manage cognitive impairment associated with conditions such as Alzheimer's disease.
Yamaguchi
Yoshimasa
Y
Research Laboratory, Zenyaku Kogyo Co., Ltd., 2-33-7 Ohizumi-machi, Nerima-ku, Tokyo 178-0062, Japan. yoshimasa_yamaguchi@mail.zenyaku.co.jp
Miyashita
Hitoshi
H
Tsunekawa
Hiroko
H
Mouri
Akihiro
A
Kim
Hyoung-Chun
HC
Saito
Kenichi
K
Matsuno
Toshiyuki
T
Kawashima
Seiichiro
S
Nabeshima
Toshitaka
T
D000284:Administration, Oral; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007276:Injections, Intraventricular; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000633:toxicity; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D007189:Indans; D010446:Peptide Fragments; D013141:Spiro Compounds; C078592:amyloid beta-protein (1-40); C511224:spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one; D012601:Scopolamine; D002795:Choline O-Acetyltransferase