PT - JOURNAL ARTICLE AU - Yoshimasa Yamaguchi AU - Hitoshi Miyashita AU - Hiroko Tsunekawa AU - Akihiro Mouri AU - Hyoung-Chun Kim AU - Kenichi Saito AU - Toshiyuki Matsuno AU - Seiichiro Kawashima AU - Toshitaka Nabeshima TI - Effects of a Novel Cognitive Enhancer, Spiro[imidazo-[1,2-<em>a</em>]pyridine-3,2-indan]-2(3<em>H</em>)-one (ZSET1446), on Learning Impairments Induced by Amyloid-β<sub>1–</sub>40 in the Rat AID - 10.1124/jpet.105.098640 DP - 2006 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1079--1087 VI - 317 IP - 3 4099 - http://jpet.aspetjournals.org/content/317/3/1079.short 4100 - http://jpet.aspetjournals.org/content/317/3/1079.full SO - J Pharmacol Exp Ther2006 Jun 01; 317 AB - We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid-β (Aβ)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 Aβ1–40 or scopolamine. The i.c.v. infusion of Aβ1–40 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. Aβ1–40-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 Aβ1–40-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 Aβ1–40-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 Aβ1–40-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. The American Society for Pharmacology and Experimental Therapeutics